Long Non-coding Rna Used For Anticancer Therapy

Abstract

The present invention provides a novel long non-coding RNA (lncRNA), which is induced by .beta.-catenin and highly expressed in cancer, a nucleic acid that suppresses expression of the lncRNA, a means for promoting or suppressing cell growth by using the lncRNA or the nucleic acid, and the like.

Description

TECHNICAL FIELD

[0001] The present invention relates to a long non-coding RNA (lncRNA) induced by .beta.-catenin in cancer cells, and showing anti-cancer cell activity by suppression of expression by nucleic acid and the like, nucleic acid used for suppressing expression of lncRNA, and the like.

BACKGROUND ART

[0002] It is known that Wnt signal is closely involved in the development, differentiation and growth of cell, and .beta.-catenin is activated and the expression of the target gene is regulated in a cell stimulated by Wnt ligand. Also, it is widely known that abnormality of Wnt signal induces cell canceration and promotes growth and differentiation of cancer cells, and metastasis and infiltration of cancer cells.

[0003] In recent years, the correlation between expression of lncRNA such as HOTAIR and the like and poor treatment prognosis of high-grade malignant cancer and the like has been reported. HOTAIR is suggested to control methylation modification of histone via Polycomb complex in cancer cells such as breast cancer and the like (non-patent document 1).

[0004] Polycomb complex is constituted of factors including histone methylation modifying enzyme EZH2, and involved in the development, differentiation and growth control of cells. In addition, the correlation between malignancy and EZH2 expression has been suggested in plural cancer types such as lymphoma and breast cancer (non-patent document 2).

[0005] Along with the development of a high-speed sequencer, new search for lncRNA has been tried mainly in human and mouse cells. Recently, large scale sequence analyses in an attempt to obtain lncRNA that binds to a Polycomb complex in mouse ES cells and human colorectal cancer cell lines have been reported (non-patent documents 3-5, patent document 1).

[0006] On the contrary, however, most of such lncRNAs are only structure predictions in silico, and many remain to be elucidated as to the functions such as relation to the growth, differentiation and metastasis of cancer cells and the like. In addition, lncRNA induced by .beta.-catenin has not been known yet.

DOCUMENT LIST

Patent Document

[0007] patent document 1: WO 2012/065143

Non-Patent Documents

[0007] [0008] non-patent document 1: Gupta et al. (2010) Nature 464, 1071-1076. [0009] non-patent document 2: Chase and Cross. (2011) Clinical Cancer Research 17, 2613-2618. [0010] non-patent document 3: Zhao et al. (2010) Molecular Cell 40, 939-953. [0011] non-patent document 4: Chu et al. (2011) Molecular Cell 44, 667-678. [0012] non-patent document 5: Guil et al. (2012) Nature Structural & Molecular Biology doi:10.1038/nsmb.2315

SUMMARY OF THE INVENTION

Problems to be Solved by the Invention

[0013] From the aspects of cancer therapy, improving effects on the growth and metastasis of high-grade malignant cancer and poor treatment prognosis are desired. For this end, a superior target and increased specificity for the target provide an effective means.

[0014] The present invention aims to provide a novel target of cancer and nucleic acid for the treatment of cancer.

Means of Solving the Problems

[0015] The present inventors have obtained a novel lncRNA, which is induced by .beta.-catenin, by performing a large-scale base sequence analysis of expressed RNA by using a high-speed sequencer in metastatic cancer cells, and found that a strong anti-cancer cell activity can be exhibited by suppressing expression of the above-mentioned lncRNA by using nucleic acid and the like.

[0016] Accordingly, the present invention provides the following invention that solves the aforementioned problem.

(1) An lncRNA consisting of a nucleotide sequence having not less than 80% identity with the nucleotide sequence shown in any of SEQ ID NOs: 1-15 and SEQ ID NOs: 38-41. (2) An lncRNA that hybridizes to a complementary strand of a nucleic acid consisting of the nucleotide sequence shown in any of SEQ ID NOs: 1-15 and SEQ ID NOs: 38-41 under stringent conditions. (3) An lncRNA consisting of the nucleotide sequence shown in any of SEQ ID NOs: 1-15 and SEQ ID NOs: 38-41. (4) A nucleic acid consisting of a nucleotide sequence complementary to the lncRNA of any one of the above-mentioned (1)-(3). (5) A double-stranded nucleic acid consisting of the lncRNA of any one of the above-mentioned (1)-(3), and a nucleic acid consisting of a nucleotide sequence complementary to the nucleotide sequence of the lncRNA. (6) A nucleic acid that suppresses expression of the lncRNA of any one of the above-mentioned (1)-(3). (7) The nucleic acid of the above-mentioned (6), which is selected from siRNA, antisense nucleic acid, shRNA or miRNA. (8) The nucleic acid of the above-mentioned (6), which is an siRNA targeting the nucleotide sequence shown in any of SEQ ID NOs: 42-50. (9) A vector expressing the nucleic acid or lncRNA of any one of the above-mentioned (1)-(8). (10) A cell introduced with the nucleic acid or lncRNA of any one of the above-mentioned (1)-(8). (11) A cell introduced with the vector of the above-mentioned (9). (12) A cell growth promoter or growth inhibitor comprising the nucleic acid or lncRNA of any one of the above-mentioned (1)-(8) as an active ingredient. (13) A diagnostic drug or a therapeutic drug for a disease caused by abnormality in cell growth, which comprises the nucleic acid or lncRNA of any one of the above-mentioned (1)-(8) as an active ingredient. (14) The diagnostic drug or therapeutic drug of the above-mentioned (13), wherein the disease is selected from gastrointestinal cancer, liver cancer, kidney cancer, lung cancer, skin cancer, breast cancer, uterine cancer, prostate cancer, urinary bladder cancer, or head and neck cancer. (15) A method of detecting expression of lncRNA, comprising using the lncRNA of any one of the above-mentioned (1)-(3). (16) A method of detecting a mutation of lncRNA, comprising using the lncRNA of any one of the above-mentioned (1)-(3). (17) A method of suppressing expression of lncRNA, comprising using the nucleic acid of any one of the above-mentioned (4)-(8). (18) A method of screening for a substance that suppresses expression or function of lncRNA, comprising using the lncRNA of any one of the above-mentioned (1)-(3).

Effect of the Invention

[0017] According to the present invention, growth, metastasis and infiltration of cancer cells that express target lncRNA can be suppressed. Using expression of target lncRNA as an index, moreover, it is possible to specify, diagnose and treat metastatic cancer cells.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1, (a) shows expression levels of lncRNA8R when siRNAs (siRNA1-3) for .beta.-catenin were introduced into SW480 cells, (b) shows expression levels of lncRNA9R when siRNAs (siRNA1-3) for .beta.-catenin were introduced into SW480 cells, (c) shows expression levels of lncRNA12R when siRNAs (siRNA1-3) for .beta.-catenin were introduced into SW480 cells, (d) shows expression levels of lncRNA13R when siRNAs (siRNA1-3) for .beta.-catenin were introduced into SW480 cells, and (e) shows expression levels of .beta.-catenin when siRNAs (siRNA1-3) for 3-catenin were introduced into SW480 cells.

[0019] FIG. 2 shows signal values of lncRNA8R in normal large intestine clinical samples, colorectal cancer cell line samples and colorectal cancer clinical samples.

[0020] FIG. 3 shows signal values of lncRNA9R in normal large intestine clinical samples, colorectal cancer cell line samples and colorectal cancer clinical samples.

[0021] FIG. 4 shows signal values of lncRNA12R in normal large intestine clinical samples, colorectal cancer cell line samples and colorectal cancer clinical samples.

[0022] FIG. 5 shows signal values of lncRNA13R in normal large intestine clinical samples, colorectal cancer cell line samples and colorectal cancer clinical samples.

[0023] FIG. 6 shows anticellular activity when siRNA for lncRNA8R was introduced into SW480 cells, wherein the dotted line shows anticellular activity of control siRNA-introduced cells, the solid line shows anticellular activity of 8R1siRNA-introduced cells, and the broken line shows anticellular activity of 8R2siRNA-introduced cells.

[0024] FIG. 7 shows anticellular activity when siRNA for lncRNA12R was introduced into SW480 cells, wherein the dotted line shows anticellular activity of control siRNA-introduced cells, the solid line shows anticellular activity of 12R#16siRNA-introduced cells, and the broken line shows anticellular activity of 12R#17siRNA-introduced cells.

[0025] FIG. 8 shows anticellular activity when siRNAs for lncRNA12R, lncRNA13R were each introduced into SW480 cells and SW620 cells.

[0026] FIG. 9 shows RNA immunoprecipitation of SW480 cells by using anti-PRC2 antibodies (EZH2, SUZ12), wherein net-like pattern shows lncRNA9R, black shows lncRNA12R, white shows TUG', gray shows MALAT1, vertical line shows HOTAIR, diagonal line shows ACTS, and shade shows SNORD15.

[0027] FIG. 10 shows RNA immunoprecipitation of SW620 cells by using anti-PRC2 antibody (SUZ12).

[0028] FIG. 11 shows colony-formability when siRNA for lncRNA12R and siRNA for lncRNA13R were each introduced into SW480 cells and SW620 cells.

[0029] FIG. 12 shows migratory ability when siRNA for lncRNA12R was introduced into SW480 cells.

MODE FOR CARRYING OUT THE INVENTION

[0030] The lncRNA in the present invention is a long single-stranded RNA induced by .beta.-catenin, which is a novel lncRNA highly expressed in cancer.

[0031] As the lncRNA of the present invention, lncRNA consisting of a nucleotide sequence having not less than 80% identity with the nucleotide sequence shown in any of SEQ ID NOs: 1-15 and SEQ ID NOs: 38-41, more preferably lncRNA consisting of a nucleotide sequence having not less than 90% identity, most preferably lncRNA consisting of a nucleotide sequence having not less than 95% (e.g., not less than 96%, not less than 97%, not less than 98%, not less than 99%) identity can be mentioned. The identity of the nucleotide sequences in the present invention can be calculated using homology calculation algorithm NCBI BLAST (National Center for Biotechnology Information Basic Local Alignment Search Tool) under the following conditions (expectancy=10; gap allowed; filtering=ON; match score=1; mismatch score=-3).

[0032] As the lncRNA of the present invention, lncRNA that hybridizes to a complementary strand of lncRNA consisting of the nucleotide sequence shown in any of SEQ ID NOs: 1-15 and SEQ ID NOs: 38-41 under stringent conditions can be mentioned. To be specific, lncRNA consisting of the nucleotide sequence shown in any of SEQ ID NOs: 1-15 and SEQ ID NOs: 38-41 can be mentioned.

[0033] In the present invention, lncRNA that hybridizes under stringent conditions includes, for example, lncRNA that can be identified by using a nucleic acid (including double-stranded nucleic acid such as cDNA, cRNA and the like) complementary to lncRNA having the nucleotide sequence shown in any of SEQ ID NOs: 1-15 and SEQ ID NOs: 38-41 or a partial fragment thereof as a probe, adding a probe RNA labeled with .gamma.-.sup.32P-ATP to a hybridization buffer composed of 20.times.SSC 7.5 mL, 1M Na.sub.2HPO.sub.4 (pH 7.2) 0.6 mL, 10% SDS 21 mL, 50.times.Denhardt's solution 0.6 mL, 10 mg/mL sonicated salmon sperm DNA 0.3 mL, reacting the mixture at 50.degree. C. overnight, washing same with 5.times.SSC/5% SDS solution at 50.degree. C. for 10 min, further washing same with 1.times.SSC/1% SDS solution at 50.degree. C. for 10 min, thereafter taking out the membrane, and exposing same to an X-ray film.

[0034] As the nucleic acid that suppresses expression of lncRNA in the present invention, any nucleic acid such as a single-stranded nucleic acid, a double-stranded nucleic acid and the like can be used as long as it is a nucleic acid containing a partial nucleotide sequence of lncRNA and/or a nucleotide sequence complementary to the nucleotide sequence and suppressing the expression of lncRNA, and a double-stranded nucleic acid is preferably used. As used herein, "suppressing the expression" is used in the meaning encompassing suppression of transcription of lncRNA of the present invention (e.g., antigene), cleavage of lncRNA (e.g., siRNA, shRNA, ribozyme), or inhibition of formation of functional lncRNA (e.g., antisense nucleic acid, miRNA).

[0035] While the partial nucleotide sequence of lncRNA to be the target sequence for the nucleic acid of the present invention is not particularly limited, for example, when the sequence of siRNA and/or shRNA is to be designed, it can be searched for by using a searching software provided on various web sites. Examples of such site include, but are not limited to, siRNA Target Finder (http://www.ambion.com/jp/techlib/misc/siRNA_finder.html) and Insert Design Tool for the pSilencer (registered trade mark) Expression Vectors (http://www.ambion.com/jp/techlib/misc/psilencer_converter.html) provided by Ambion, and GeneSeer (http://codex.cshl.edu/scripts/newsearchhairpin.cgi) provided by RNAi Codex.

[0036] In the present invention, the double-stranded nucleic acid refers to a nucleic acid wherein two strands form a pair to have a double strand forming part. The double strand forming part refers to a part wherein nucleotide or a derivative thereof constituting a double-stranded nucleic acid constitutes base pairs to form a double strand. The double strand forming part generally contains 15-27 base pairs, preferably 15-25 base pairs, more preferably 15-23 base pairs, further preferably 15-21 base pairs, particularly preferably 15-19 base pairs.

[0037] A single-stranded nucleic acid constituting a double-stranded nucleic acid is generally composed of 15-30 bases, preferably 15-29 bases, more preferably 15-27 bases, further preferably 15-25 bases, particularly preferably 17-23 bases, most preferably 19-21 bases.

[0038] When the double-stranded nucleic acid of the present invention has an additional nucleotide or a nucleotide derivative that does not form a double strand on the 3'-side or 5'-side following the double strand forming part, these overhanging parts may be a ribonucleotide, a deoxyribonucleotide or a derivative thereof.

[0039] A double-stranded nucleic acid having an overhanging part composed of 1-4 bases, generally 1-3 bases, preferably two bases and more preferably dTdT or UU at the 3'-end or 5'-end of at least one of the strands is used. The overhanging part can be formed on antisense strand alone, sense strand alone, or both antisense strand and sense strand. A double-stranded nucleic acid having an overhanging part on both antisense strand and sense strand is preferably used. As used herein, the "sense strand" means a strand having a sequence homologous to a target sequence of lncRNA, and the "antisense strand" means a strand having a sequence complementary to the target sequence. In addition, a sequence continued from the double strand forming part, which is partially or fully identical with the target sequence, or a sequence continued from the double strand forming part, which is identical with a base sequence of a complementary strand of the target sequence can also be used. As the double-stranded nucleic acid of the present invention, a nucleic acid molecule that forms the above-mentioned double-stranded nucleic acid by the action of ribonuclease, for example, such as Dicer and the like (WO 2005/089287), a double-stranded nucleic acid free of a 3'-end or 5'-end overhanging part and the like can also be used.

[0040] As the nucleic acid of the present invention, moreover, a single-stranded nucleic acid can also be used. Such nucleic acid having a suppressive activity on lncRNA expression, wherein 1-3 bases, preferably 1-2 bases, more preferably 1 base, is/are substituted, deleted or added, can also be used. In addition, nucleic acids of not more than 30 bases, preferably not more than 29 bases, more preferably not more than 27 bases, further preferably not more than 25 bases, particularly preferably not more than 23 bases, including the above nucleic acid, can be mentioned.

[0041] In addition, the sense strand and antisense strand of the above-mentioned double-stranded nucleic acid may be linked via a spacer sequence to give a single-stranded nucleic acid. Such single-stranded nucleic acid is preferably a single-stranded nucleic acid such as shRNA having a double strand forming part due to a stem loop structure and the like. A single-stranded nucleic acid having a stem loop structure generally has a 50-70 base length.

[0042] As another single-stranded nucleic acid, an antisense nucleic acid can be mentioned. The antisense nucleic acid may be DNA or RNA, or DNA/RNA chimera. When the antisense nucleic acid is DNA, RNA:DNA hybrid formed by target RNA and antisense DNA is recognized by endogenous RNase H and can cause selective degradation of the target RNA.

[0043] The nucleic acid of the present invention may be a nucleic acid having not more than 70 base length, preferably not more than 50 base length, more preferably not more than 30 base length, which is designed to form the above-mentioned single-stranded nucleic acid or double-stranded nucleic acid by the action of ribonuclease and the like.

[0044] The molecule constituting the nucleic acid of the present invention may be any molecule as long as it is a molecule wherein nucleotides or molecules having function equivalent to that of the nucleotide are polymerized, and examples thereof include RNA which is a polymer of ribonucleotides, DNA which is a polymer of deoxyribonucleotides, chimeric nucleic acid composed of RNA and DNA, and a nucleotide polymer wherein at least one nucleotide for these nucleic acids is substituted by a molecule having function equivalent to that of the nucleotide. siRNA, sh (short hairpin) RNA, miRNA and a derivative thereof containing at least one molecule having function equivalent to that of nucleotide therein for these nucleic acids are also included in the nucleic acid of the present invention. Uracil (U) in RNA can be unambiguously interpreted as thymine (T) in DNA.

[0045] Examples of the molecule having function equivalent to that of nucleotide include nucleotide derivative and the like. The nucleotide derivative may be any molecule as long as it is a molecule obtained by modifying nucleotide and, for example, a molecule obtained by modifying ribonucleotide or deoxyribonucleotide and the like are preferably used to improve or stabilize nuclease resistance, increase affinity to complementary strand nucleic acid, increase cell permeability, or visualize, as compared to RNA or DNA.

[0046] Examples of the nucleotide derivative include sugar moiety-modified nucleotide, phosphodiester bond-modified nucleotide, base-modified nucleotide, nucleotide wherein at least one of the sugar moiety, phosphodiester bond and base is modified, and the like.

[0047] As the sugar moiety-modified nucleotide, any can be used as long as a part of or whole chemical structure of the sugar of nucleotide is modified with or substituted by any substituent, or substituted by any atom, and 2'-modified nucleotide is preferably used.

[0048] Examples of the 2'-modified nucleotide include 2'-modified nucleotide wherein a 2'-OH group of ribose is substituted by substituent(s) selected from the group consisting of H, OR, R, R' OR, SH, SR, NH.sub.2, NHR, NR.sub.2, N.sub.3, CN, F, Cl, Br and I (R is alkyl or aryl, preferably alkyl having 1-6 carbon atoms, and R' is alkylene, preferably alkylene having 1-6 carbon atoms), and the 2'-OH group is preferably substituted by F or a methoxy group. Examples thereof also include 2'-modified nucleotide substituted by substituent(s) selected from the group consisting of a 2-(methoxy)ethoxy group, a 3-aminopropoxy group, a 2-[(N,N-dimethylamino)oxy]ethoxy group, a 3-(N,N-dimethylamino)propoxy group, a 2-[2-(N,N-dimethylamino)ethoxy]ethoxy group, a 2-(methylamino)-2-oxoethoxy group, a 2-(N-methylcarbamoyl)ethoxy group and a 2-cyanoetoxy group, and the like.

[0049] Examples of the sugar moiety-modified nucleotide include bridged artificial nucleic acid (Bridged Nucleic Acid, BNA) having two cyclic structures by introduction of a bridged structure into the sugar moiety, and specific examples thereof include locked artificial nucleic acid (Locked Nucleic Acid, LNA) wherein the 2'-position oxygen atom and the 4'-position carbon atom are bridged via methylene, ethylene bridged artificial nucleic acid (Ethylene bridged nucleic acid, ENA) [Nucleic Acid Research, 32, e175(2004)] and the like. Furthermore, peptide nucleic acid (PNA) [Acc. Chem. Res., 32, 624 (1999)], oxypeptide nucleic acid (OPNA) [J. Am. Chem. Soc., 123, 4653 (2001)], peptide ribonucleic acid (PRNA) [J. Am. Chem. Soc., 122, 6900 (2000)] and the like can also be mentioned.

[0050] The phosphodiester bond-modified nucleotide may be any as long as a part of or whole chemical structure of the phosphodiester bond of nucleotide is modified with or substituted by any substituent, or substituted by any atom. Examples thereof include a nucleotide wherein a phosphodiester bond is substituted by a phosphorothioate bond, a nucleotide wherein a phosphodiester bond is substituted by a phosphorodithioate bond, a nucleotide wherein a phosphodiester bond is substituted by an alkylphosphonate bond, a nucleotide wherein a phosphodiester bond is substituted by a phosphoroamidate bond and the like.

[0051] The base-modified nucleotide may be any as long as a part of or whole chemical structure of the base of nucleotide is modified with or substituted by any substituent, or substituted by any atom. Examples thereof include a nucleotide wherein an oxygen atom in the base is substituted by a sulfur atom, a nucleotide wherein a hydrogen atom is substituted by an alkyl group having 1-6 carbon atoms, a nucleotide wherein a methyl group is substituted by hydrogen or an alkyl group having 2-6 carbon atoms, a nucleotide wherein an amino group is protected by a protecting group such as an alkyl group having 1-6 carbon atoms, an alkanoyl group having 1-6 and the like.

[0052] Furthermore, examples of the nucleotide derivative include a nucleotide derivative wherein other chemical substance such as lipid, phospholipid, phenazine, folate, phenanthridine, anthraquinone, acridine, fluorescein, rhodamine, coumarin, pigment and the like is added to nucleotide or nucleotide derivative, in which at least one of sugar moiety, phosphodiester bond and base is modified. Specific examples thereof include 5'-polyamine-added nucleotide derivative, cholesterol-added nucleotide derivative, steroid-added nucleotide derivative, bile acid-added nucleotide derivative, vitamin-added nucleotide derivative, Cy5-added nucleotide derivative, Cy3-added nucleotide derivative, 6-FAM-added nucleotide derivative, biotin-added nucleotide derivative and the like.

[0053] In addition, the nucleotide derivative may form a bridged structure such as alkylene structure, peptide structure, nucleotide structure, ether structure, ester structure, and a structure combining at least one of these and the like with other nucleotide or nucleotide derivative in the nucleic acid.

[0054] The nucleic acid of the present invention may be constituted of any nucleotide or a derivative thereof as long as it is a nucleic acid having function equivalent to that of a nucleic acid consisting of a partial nucleotide sequence of lncRNA or a nucleic acid consisting of a nucleotide sequence complementary to the nucleotide sequence of the nucleic acid. That is, a nucleic acid consisting of a partial nucleotide sequence of lncRNA or a nucleic acid consisting of a nucleotide sequence complementary to the nucleotide sequence of the nucleic acid may be a nucleic acid wherein the nucleotide constituting the nucleotide sequence is substituted by ribonucleotide, deoxyribonucleotide or a derivative thereof, which has function equivalent to that of the nucleotide.

[0055] A production method of the nucleic acid of the present invention is not particularly limited, and examples thereof include a method using known chemical synthesis, an enzymatic transcription method and the like. Examples of the method using known chemical synthesis include phosphoramidite method, phosphorothioate method, phosphotriester method, CEM method [Nucleic Acid Research, 35, 3287 (2007)] and the like. For example, it can be synthesized by ABI3900 High Throughput Nucleic Acid Synthesizer (manufactured by Applied Biosystems). After completion of the synthesis, dissociation from the solid phase, removal of protecting group, purification of the object product and the like are performed. By purification, a nucleic acid with a purity of not less than 90%, preferably not less than 95%, is desirably obtained. In the case of a double-stranded nucleic acid, synthesized and purified sense strand and antisense strand may be mixed at a suitable ratio, for example, 0.1-10 equivalents, preferably 0.5-2 equivalents, more preferably 0.9-1.1 equivalents, further preferably an equimolar amount, of sense strand is mixed with 1 equivalent of antisense strand and the mixture may be annealed before use, or may be directly used by omitting the step of annealing the mixture. Annealing may be performed under any conditions as long as a double-stranded nucleic acid can be formed. Generally, it includes mixing nearly equimolar amounts of the sense strand and the antisense strand, heating the mixture at about 94.degree. C. for about 5 min, and slowly cooling to room temperature. As an enzymatic transcription method for production of the nucleic acid of the present invention, a method including transcription using a plasmid or DNA having the object nucleotide sequence as a template, and phage RNA polymerase, for example, T7, T3, or SP6 RNA polymerase can be mentioned.

[0056] Examples of the method for introduction of the nucleic acid of the present invention into a cell include a method using a carrier for transfection, preferably a cationic carrier such as cationic liposome and the like, calcium phosphate method, electroporation method, microinjection method and the like.

[0057] It is also possible to use, instead of the nucleic acid of the present invention, a vector capable of expressing the nucleic acid by introduction into the cell. To be specific, the nucleic acid and the like can be expressed by inserting a sequence encoding the nucleic acid of the present invention into the downstream of a promoter in an expression vector to construct an expression vector, and introducing same into the cell.

[0058] As an expression vector, a recombinant virus vector produced by inserting a sequence encoding the nucleic acid of the present invention into the downstream of a promoter in a virus vector, and introducing the vector into a packaging cell can be used. Examples of the virus vector include retrovirus vector, lentivirus vector, adenovirus vector, adeno-associated virus vector, Sendai virus vector and the like.

[0059] Expression of lncRNA can be suppressed by introducing such single-stranded nucleic acid or double-stranded nucleic acid into the cell.

[0060] Also, the lncRNA expression suppressive activity of the single-stranded nucleic acid or double-stranded nucleic acid of the present invention can be evaluated by transfecting the nucleic acid and the like into cultured cancer cells and the like by using a cationic liposome and the like, culturing same for a given time, and quantifying the expression level of lncRNA in the cancer cells by RT-PCR. The suppressive effect on cell proliferation can be evaluated by calculating the viable cell number of the cells introduced with the single-stranded nucleic acid or double-stranded nucleic acid of the present invention.

[0061] The method for detecting the expression of lncRNA of the present invention may be any as long as the presence of lncRNA in a sample can be detected. Examples thereof include (1) Northern hybridization [Science 294, 853-858 (2001)], (2) dot blot hybridization [Molecular Cloning, 3rd ed.], (3) in situ hybridization [Methods in Enzymology, 254, 419 (1995)], (4) quantitative PCR [Nucleic Acids Research, 32, e43 (2004)], (5) differential hybridization [Trends Genet., 7, 314 (1991)], (6) microarray [Genome Res., 6, 639 (1996)], (7) ribonuclease protection assay [mirVana miRNA Detection Kit (manufactured by Ambion)] and the like.

[0062] The method for detecting a mutation of lncRNA of the present invention may be any as long as a mutation of the nucleotide sequence of lncRNA in a sample can be detected. Examples thereof include a method of detecting a heteroduplex formed by hybridization of a nucleic acid having a non-mutant nucleotide sequence and a nucleic acid having a mutant nucleotide sequence, a method of detecting the presence or absence of mutation by directly sequencing a nucleotide sequence derived from a sample and the like.

[0063] Examples of the method of detecting a heteroduplex include methods such as (1) heteroduplex detection method by polyacrylamide gel electrophoresis [Trends genet., 7, 5 (1991)], (2) single strand conformation polymorphism analysis method [Genomics, 16, 325-332 (1993)], (3) chemical cleavage of mismatches (CCM) [Human Genetics (1996), Tom Strachan and Andrew P. Read, BIOS Scientific Publishers Limited], (4) enzymatical cleavage of mismatches [Nature Genetics, 9, 103-104 (1996)], (5) denaturing gel electrophoresis [Mutat. Res., 288, 103-112 (1993)] and the like.

[0064] As a method of screening for a substance that promotes or suppresses expression or function of lncRNA by using lncRNA of the present invention, for example, a substance that promotes or suppresses expression or function of lncRNA can be screened for by selecting a nucleotide sequence as a screening target from the nucleotide sequence of lncRNA of the present invention, and utilizing a cell expressing a nucleic acid having the nucleotide sequence.

[0065] As a cell expressing a nucleic acid having the nucleotide sequence of lncRNA, which is used for screening, a transformed cell obtained by introducing a vector expressing a nucleic acid having the nucleotide sequence into a host cell such as an animal cell and the like, a cell directly introduced with a nucleic acid having the nucleotide sequence without using a vector and the like can also be used.

[0066] As a specific screening method, a method using, as an index, changes in the expression level of lncRNA to be the screening target can be mentioned.

[0067] A test substance is contacted with a cell expressing a nucleic acid having the nucleotide sequence, and a substance that promotes or suppresses expression of lncRNA is obtained by using changes in the expression level of the nucleic acid as an index.

[0068] The present invention also relates to a pharmaceutical composition containing, as an active ingredient, a nucleic acid such as single-stranded nucleic acid, double-stranded nucleic acid and the like or a vector that suppresses expression of the above-mentioned lncRNA of the present invention. The pharmaceutical composition can further contain a carrier effective for intracellular transfer of the nucleic acid. The pharmaceutical composition of the present invention can be used for the treatment or prophylaxis of cancer diseases. Examples of the cancer include solid tumors such as gastrointestinal cancer, liver cancer, kidney cancer, lung cancer, skin cancer, breast cancer, uterine cancer, prostate cancer, urinary bladder cancer, head and neck cancer and the like.

[0069] Examples of the carrier effective for intracellular transfer of a nucleic acid include a cationic carrier. Examples of the cationic carrier include cationic liposome, cationic polymer and the like. In addition, as a carrier effective for intracellular transfer of a nucleic acid, a carrier utilizing a virus envelope may be used. As the cationic liposome, a liposome containing 2-O-(2-diethylaminoethyl)carbamoyl-1,3-O-dioleoylglycerol (hereinafter to be also referred to as liposome A), Oligofectamine (Invitrogen), Lipofectine (Invitrogen), Lipofectamine (Invitrogen), Lipofectamine 2000 (Invitrogen), DMRIE-C (Invitrogen), GeneSilencer (Gene Therapy Systems, Inc.), TransMessenger (QIAGEN), TransIT TKO (Mirus Bio LLC) and the like are preferably used. As the cationic polymer, JetSI (Qbiogene), Jet-PEI (polyethylenimine; Qbiogene) and the like are preferably used. As a carrier utilizing a virus envelope, GenomeOne (HVJ-E liposome; Ishihara Sangyo Kaisha, Ltd.) and the like are preferably used.

[0070] A composition containing a single-stranded nucleic acid, double-stranded nucleic acid or vector to be contained in the pharmaceutical composition of the present invention and the above-mentioned carrier can be prepared by a method known to those of ordinary skill in the art. For example, it can be prepared by mixing a suitable concentration of a carrier dispersion and a single-stranded nucleic acid, double-stranded nucleic acid or vector solution. When a cationic carrier is used, the composition can be prepared with ease by mixing in an aqueous solution by a conventional method, since a single-stranded nucleic acid, double-stranded nucleic acid or vector is negatively charged in an aqueous solution. Examples of the aqueous solvent used for the preparation of the composition include water for injection, distilled water for injection, electrolyte fluids such as saline and the like, sugar solutions such as glucose solution, maltose solution and the like, and the like.

[0071] The conditions of pH, temperature and the like for the preparation of the composition can be appropriately selected by those of ordinary skill in the art. For example, liposome A can be prepared by gradually adding oligo double-stranded RNA solution in 10% aqueous maltose solution to 16 mg/ml liposome dispersion in 10% aqueous maltose solution at pH 7.4, 25.degree. C. with stirring.

[0072] The composition can be processed into a uniform composition where necessary by performing a dispersion treatment using an ultrasonic dispersion apparatus, a high-pressure emulsification apparatus and the like. An optimal method and conditions for the preparation of a composition containing a carrier and a single-stranded nucleic acid, double-stranded nucleic acid or vector vary depending on the carrier to be used, and those of ordinary skill in the art can select an optimal method for the carrier to be used, without being caught by the above-mentioned methods.

[0073] As the pharmaceutical composition of the present invention, a liposome comprised of complex particles comprising a single-stranded nucleic acid, double-stranded nucleic acid or vector and a lead particle as constituent components, and a lipid membrane for coating the complex particles, wherein constituent components of the lipid membrane can be solved in a polar organic solvent, and wherein the polar organic solvent can be contained in a liquid at such a concentration that the constituent components of the lipid membrane are dispersible and the complex particles are dispersible is also used preferably. Examples of the lead particle include a fine particle containing lipid assembly, liposome, emulsion particle, polymer, metal colloid, fine particle preparation and the like as a constituent component, and preferable examples thereof include a fine particle containing a liposome as a constituent component. The lead particle in the present invention may contain, as a constituent component, a complex of a combination of two or more from lipid assembly, liposome, emulsion particle, polymer, metal colloid, fine particle preparation and the like, and may contain, as a constituent component, a complex of a combination of lipid assembly, liposome, emulsion particle, polymer, metal colloid, fine particle preparation and the like, and other compound (e.g., sugar, lipid, inorganic compound etc.).

[0074] Examples of the lipid membrane for coating the complex particles include those containing neutral lipid and polyethylene glycol-phosphatidylethanolamine and the like as constituent components.

[0075] The liposome can be prepared according to the method described in, for example, WO 2006/080118 and the like.

[0076] A suitable mixing ratio of a single-stranded nucleic acid, double-stranded nucleic acid or vector and a carrier to be contained in the pharmaceutical composition of the present invention is 1-200 parts by weight of a carrier per 1 part by weight of a single-stranded nucleic acid, double-stranded nucleic acid or vector. It is preferably 2.5-100 parts by weight, more preferably 10-20 parts by weight, of a carrier per 1 part by weight of a single-stranded nucleic acid, double-stranded nucleic acid or vector.

[0077] The pharmaceutical composition of the present invention may contain, besides the above-mentioned carrier, a pharmaceutically acceptable carrier, a diluent and the like. A pharmaceutically acceptable carrier, a diluent and the like are essentially chemically inert and harmless compositions and do not at all affect the biological activity of the pharmaceutical composition of the present invention. Examples of such carrier or diluent include, but are not limited to, a salt solution, a sugar solution, a glycerol solution, ethanol and the like.

[0078] The pharmaceutical composition of the present invention contains the complex in an amount effective for the treatment or prophylaxis of diseases, and is provided in a form permitting appropriate administration to the patients. The formulation of the pharmaceutical composition of the present invention may be, for example, a liquid such as injection, eye drop, inhalation and the like, or an external preparation such as ointment, lotion and the like.

[0079] In the case of a liquid, the concentration range of the pharmaceutical composition of the present invention is generally 0.001-25%(w/v), preferably 0.01-5%(w/v), more preferably 0.1-2%(w/v). The pharmaceutical composition of the present invention may contain an adequate amount of any pharmaceutically acceptable additive, for example, emulsifying aid, stabilizer, isotonizing agent, pH adjuster and the like. Any pharmaceutically acceptable additive can be added in a suitable step, which may be before or after dispersing of the complex.

[0080] A freeze-dried formulation can be prepared by a dispersion treatment of a single-stranded nucleic acid, double-stranded nucleic acid or vector and a carrier, and a freeze-drying treatment thereafter. The freeze-drying treatment can be performed by a conventional method. For example, a given amount of a complex solution after the above-mentioned dispersion treatment is dispensed to a vial container under sterile conditions, predried at about -40 to -20.degree. C. for about 2 hr, primarily dried at about 0-10.degree. C. under reduced pressure, then secondarily dried at about 15-25.degree. C. under reduced pressure for lyophilization. Then, for example, the inside of the vial is purged with nitrogen gas, and the vial is capped to give a freeze-dried formulation of the pharmaceutical composition of the present invention.

[0081] The pharmaceutical composition of the present invention can be redissolved by the addition of any suitable solution and used. Examples of such solution include water for injection, electrolyte fluids such as saline and the like, glucose solution, other conventional infusion solutions and the like. While the liquid amount of the solution varies depending on the use and the like and is not particularly limited, 0.5- to 2-times the amount before freeze-drying, or not more than 500 ml, is preferable.

[0082] The pharmaceutical composition of the present invention can be administered to animals including human by, for example, intravenous administration, intraarterial administration, oral administration, intratissue administration, transdermal administration, transmucosal administration or transrectal administration, and is preferably administered by an appropriate method according to the symptom of patients. In particular, intravenous administration, transdermal administration, and transmucosal administration are preferably used. It can also be locally administered by, for example, local administration into cancer and the like. Examples of the dosage form suitable for these administration methods include various injections, oral preparations, drip infusions, absorbents, eye drops, ointments, lotions, suppositories and the like.

[0083] While the dose of the pharmaceutical composition of the present invention is desirably determined in consideration of the drug, dosage form, condition of patient such as age, body weight and the like, administration route, nature and level of diseases and the like, it is generally 0.1 mg-10 g/day, preferably 1 mg-500 mg/day, for an adult, in the mass of a single-stranded nucleic acid, double-stranded nucleic acid or vector. In some cases, an amount not more than this may be sufficient, or conversely, a dose not less than this may be necessary. It can be administered one to several times per day, and can also be administered at an interval of one day-several days.

[0084] The present invention is explained in the following by referring to Examples, which are not to be construed as limitative.

EXAMPLES

Example 1

Obtainment of Novel lncRNA Induced by .beta.-Catenin in Cancer Cell

[0085] 1-1 Identification Method of Novel lncRNA

[0086] To colorectal cancer cell line SW480 (3.times.10.sup.5 cells) was added 20 nM each of siRNA (Life Technologies, Stealth RNAi 1299003) for .beta.-catenin or control siRNA (Life Technologies, Stealth RNAiNegative control 12935-112) by using HiPerFect Transfection Reagent (QUIAGEN) and according to the attached protocol, and total RNA was recovered by using TRIzol (Life Technologies) 48 hr later. Each RNA sample was prepared according to Directional mRNA-seq sample preparation protocol (Illumina, Inc.) and analyzed using Genome Analyzer IIx, and RNA expression in all genomic regions was confirmed. The analysis software used was TOPHAT analysis (Bioinformatics, 2009, 25 (9) p 1105).

[0087] As a result, a region where RNA expression level decreases due to siRNA for .beta.-catenin, which is accompanied by a region within 5 kb from said region where binding of .beta.-catenin can be confirmed, was identified as a transcription product under regulation of .beta.-catenin. The binding of .beta.-catenin was confirmed by ChIP-seq. ChIP followed a method of using the anti-.beta.-catenin antibody of Santa Cruz Biotechnology, Inc. (sc-7199 and Cancer Sci. 2008, 99 (6) p 1139). For sequence analysis, Genome Analyzer IIx and ChIP-seq Sample Prep kit (Illumina, Inc.) were used. The analysis software used was Model-based Analysis for ChIP-seq (MACS, Genome Biol (2008) vol. 9 (9) pp. R137).

1-2 Full-Length Nucleotide Sequence of Novel lncRNA

[0088] Using Marathon cDNA Amplification Kit (Clontech Laboratories, Inc.), the terminal sequence of lncRNA identified above was determined. In addition, using Hiseq2000 and Paired-End mRNA-seq kit (Illumina, Inc.), sequence analysis was performed, cDNA was cloned by TOPHAT analysis, and the full-length nucleotide sequence of lncRNA (SEQ ID NOs: 1-15 and SEQ ID NOs: 38-41) was determined. The splicing variants corresponding to the respective SEQ ID NOs were named as follows.

[0089] SEQ ID NO: 1: 7F, SEQ ID NO: 2: 8F Variant 1, SEQ ID NO: 3: 8F Variant 2, SEQ ID NO: 4: 8F Variant 3, SEQ ID NO: 5: 8F Variant 4, SEQ ID NO: 6: 8R Variant 1, SEQ ID NO: 7: 8R Variant 2, SEQ ID NO: 8: 9R, SEQ ID NO: 9: 12R Variant 1, SEQ ID NO: 10: 12R Variant 2, SEQ ID NO: 11: 13R Variant 1, SEQ ID NO: 12: 13R Variant 2, SEQ ID NO: 13: 13R Variant 3, SEQ ID NO: 14: 14R Variant 1, SEQ ID NO: 15: 14R Variant 2, SEQ ID NO: 38: 12R Variant 3, SEQ ID NO: 39: 12R Variant 4, SEQ ID NO: 40: 12R Variant 5, SEQ ID NO: 41: 13R Variant 3

Example 2

Induction of Novel lncRNA by .beta.-Catenin

[0090] To confirm that novel lncRNA obtained in Example 1 is induced by .beta.-catenin, according to the method of Example 1-1, siRNA for .beta.-catenin or control siRNA was added to colorectal cancer cell line SW480 and the mixture was cultured, after which total RNA was recovered, and the expression level of novel lncRNA shown in Example 1 and .beta.-catenin was each measured by quantitative RT-PCR method. The primers used are shown in Table 1. Primers 8RF and 8RR (SEQ ID NOs: 16, 17) were used for the detection of lncRNA8R, primers 9RF and 9RR (SEQ ID NOs: 18, 19) were used for the detection of lncRNA9R, primers 12RF and 12RR (SEQ ID NOs: 20, 21) were used for the detection of lncRNA12R, and primers 13RF and 13RR (SEQ ID NOs: 22, 23) were used for the detection of lncRNA13R. As a result, the expressions of lncRNA decreased along with decreasing expression of .beta.-catenin in lncRNA8R, lncRNA9R, lncRNA12R and lncRNA13R (FIG. 1).

TABLE-US-00001 TABLE 1 SEQ ID Sequence No. 5'--3' Name 16 CTGGGTGGCTCCTCTCAACC 8RF 17 CCAAAGGGACCCACATCGAC 8RR 18 GCTGATCCCAGGCCCTACCT 9RF 19 GAATGCCTCCCGGTCCTTCT 9RR 20 CCCAACCACGTCTCTCACCA 12RF 21 TTCAAAGAGCACAGCTGCACA 12RR 22 GATTCAACAGCCCACGCTGA 13RF 23 ATGCCACCTGCGAGAGGAAG 13RR 28 GACGGAGGTTGAGATGAAGC MALAT1_F 29 ATTCGGGGCTCTGTAGTCCT MALAT1_R 30 TCCCGGAGGTGCTCTCAATC HOTAIR_F 31 GGGCTCCCTCTCTCCACTCC HOTAIR_R 32 TTGCCCAGGTGGCCTACTCT SNORD15A_F 33 CCTTCTCAGACAAATGCCTCTAAGT SNORD15A_R 34 AGAAGGAGATCACTGCCCTGGCACC ACTB_F 35 CCTGCTTGCTGATCCACATCTGCTG ACTB_R 36 CAAGCACTACCACCAGCACTGTTAC TUG1_F 37 GCAATCAGGAGGCACAGGACATAAT TUG1_R

Example 3

Expressions of lncRNA8R, lncRNA9R, lncRNA12R and lncRNA13R in Cancer Cells and Cancer Tissues

[0091] The data of public experimental results "GSE23768" and "Series GSE16125" using Human Exon 1.0 ST Array (Affymetrix, Inc.) were obtained from Gene Expression Omnibus (GEO) (National Center for Biotechnology and Information (NCBI)), and the expression of lncRNA8R, lncRNA9R, lncRNA12R and lncRNA13R in cancer cells and cancer tissues was analyzed. The geometric mean of signal values for 17 probes designed in the minus(-) strand of human chromosome region "chromosome 1: 3217233-3231768" of lncRNA8R obtained in Example 1, the geometric mean of signal values for 4 probes designed in the minus(-) strand of human chromosome region "chromosome 11: 2181184-2192608" of lncRNA9R, the geometric mean of signal values for 28 probes designed in the minus(-) strand of human chromosome region "chromosome 2: 171178123-171264570" of lncRNA12R and the geometric mean of signal values for 7 probes designed in the minus(-) strand of human chromosome region "chromosome 2: 171264761-171277160" of lncRNA13R were calculated. As a result, it was confirmed that all expressions were promoted in colorectal cancer samples (FIGS. 2-5).

Example 4

Suppressive Effect of Cell Growth by Suppressing Expression of lncRNA8R, lncRNA12R and lncRNA13R

[0092] siRNA (Stealth RNAi(8R1, 8R2), Life Technologies) for lncRNA8R obtained in Example 1 was introduced into colorectal cancer cell line SW480 by a method similar to that in Example 1. The sequence of siRNA used and the sequence of its target lncRNA8R are shown in Table 2 (SEQ ID NOs: 24 and 47, 25 and 48). As control siRNA, Stealth RNAi Negative Control Medium GC duplex#2 (Life Technologies, 12935-112) was used. Cell proliferation was measured using Cell Counting Kit-8 (Dojindo Laboratories) from day 0 after siRNA introduction. As a result, the growth of colorectal cancer cells was suppressed by decreasing the expression of lncRNA8R (FIG. 6).

[0093] In addition, using lentivirus vector pLK0.1 puro lentivirus vector (Addgene), shRNAs (12R#16, 12R#17) for lncRNA12R obtained in Example 1 were each introduced into colorectal cancer cell line SW480 by a conventional method. The sequence of oligo DNA used to design shRNA used and the sequence of its target lncRNA12R are shown in Table 3 (SEQ ID NOs: 26 and 49, 27 and 50). Cell proliferation was measured using Cell Counting Kit-8 (Dojindo Laboratories) from day 0 after introduction. As a result, the growth of colorectal cancer cells was suppressed by decreasing the expression of lncRNA12R (FIG. 7).

[0094] Furthermore, various siRNAs for lncRNA12R and lncRNA13R (custom synthesized siRNAs, GeneDesign Inc.) were each introduced into colorectal cancer cell line SW480 and colorectal cancer-derived lymph node metastasis cell line SW620 (1.2.times.10.sup.4 cells) to a final concentration of 50 nM by using Lipofectamine 2000 (Life Technologies) and according to the attached protocol. The target sequences of siRNA used are shown in Table 4 (SEQ ID NOs: 42-46). The control siRNA used was AllStars Negative Control siRNA (QUIAGEN, 1027281). After 72 hr of siRNA introduction, the viable cell number was measured using CellTiter-Glo Luminescent Cell Viability Assay kit (Promega Corporation), the anticellular activity was evaluated by calculating the survival rate relative to control siRNA. As a result, the growth of colorectal cancer cells was suppressed by decreasing the expression of lncRNA12R and lncRNA13R (FIG. 8).

[0095] From the above, a suppressive effect on the cell growth by the suppression of expression of lncRNA8R, lncRNA12R and lncRNA13R was confirmed.

TABLE-US-00002 TABLE 2 SEQ ID Sequence No. 5'--3' Name 24 UUCUGGAUGUGGUUCAGUGGACUGG 8R1 26 AUAGGAGCGAAUGUGAACACUGUUC 8R2 47 CCAGUCCACUGAACCACAUCCAGAA SR1target 48 GAACAGUGUUCACAUUCGCUCCUAU SR2target

TABLE-US-00003 TABLE 3 SEQ ID Sequence No. 5'--3' Name 26 GCAAATCAGTGTTGGCCATCT 12R#16 27 GGTGTCTACATGGCAGCATAA 12B#17 49 GCAAAUCAGUGUUGGCCAUCU 12R#16target 50 GGUGUCUACAUGGCAGCAUAA 12R#17target

TABLE-US-00004 TABLE 4 SEQ ID Sequence No. 5'--3' Name 42 CAGUGGCUGGUAUUACAGGAA 12R#506 43 AAGGAAAAAGUUCUCCAUAAA 12R#3950 44 UAGGGAGAAGAUAAUCAGAUA 12R#f16175 45 CCCCCCCAGCAUGGAAAUAAA 13R#9443 46 UUCCAGUUUCAGAAAAGAUUA 13R#11616

Example 5

Binding of Novel lncRNA to PRC2 in Cancer Cells

[0096] To show that novel lncRNA obtained in Example 1 binds to Polycomb Recessive Complex 2 (PRC2), RNA chromatin immunoprecipitation (RIP-ChIP) experiment using antibodies against EZH2 and SUZ12, which are the constituent components of PRC2, was performed. A cell extract was prepared from SW480 cell line, control IgG (Sigma-Aldrich Corporation, catalog No. A-6154), anti-EZH2 antibody (Active Motif, catalog No. 39933), and anti-SUZ12 antibody (Abcam plc, catalog No. ab12073) were used. The method followed Nature Protocol 2006 vol 1 NO12011.12.1.

[0097] cDNA was prepared from the obtained RNA by using SuperScript III (Invitrogen). Quantitative RT-PCR was performed using specific primers to each of lncRNA9R and lncRNA12R obtained in Example 1, and TUG1, MALAT1, HOTAIR, ACTB and SNORD15, which are known lncRNAs. The primer sequences used are shown in Table 1 (SEQ ID NOs: 18-21, 28-37). As a result, it was shown that lncRNA9R and lncRNA12R coprecipitate with SUZ12 antibody and EZH2 antibody and bind to PRC2 (FIG. 9).

[0098] Furthermore, to comprehensively clarify ncRNA binding to PRC2 in cancer cell line, RNA chromatin immunoprecipitation-sequencing (RIP-seq) experiment was performed using an antibody against SUZ12 which is the constituent component of PRC2. A nuclear extract was prepared from SW620 cell line, and control IgG (Sigma-Aldrich Corporation, catalog No. A-6154), and an anti-SUZ12 antibody (Abcam plc, catalog No. ab12073) were used. RIP method followed partly-altered Nature Protocol 2006 vol 1 NO12011.12.1.

[0099] Sequencing library was prepared from the obtained RNA by using TruSeq RNA Sample Preparation Kits (Illumina, Inc.), and sequencing was performed using sequencer Hiseq2000 (Illumina, Inc.). After analysis by TOPHAT and normalization by the number of read mapped on mitochondria, the number of the read mapped in the lncRNA region was counted, and the ratio of the read number with anti-SUZ12 antibody to that with control IgG was calculated, based on which the bindability to PRC2 was evaluated. GAPDH (Glyceraldehyde.sub.--3-phosphate_dehydrogenase gene) was used as the negative control and TUG1 (Taurine upregulated gene 1 gene) was used as the positive control. As a result, it was shown that lncRNA13R strongly binds to PRC2 (FIG. 10).

Example 6

Suppressive Effect of Colony Formability of Cancer Cells by Suppression of Expression of lncRNA12R and lncRNA13R

[0100] siRNAs for lncRNA12R and lncRNA13R (custom synthesized siRNAs, GeneDesign Inc.) were each introduced into colorectal cancer cell line SW480 and colorectal cancer-derived lymph node metastasis cell line SW620 (3.times.10.sup.5 cells) to a final concentration of 50 nM by using Lipofectamine 2000 (Life Technologies) and according to the attached protocol. The target sequences of siRNA used are shown in Table 4 (SEQ ID NOs: 42, 45). The control siRNA used was AllStars Negative Control siRNA (QUIAGEN, 1027281). After 24 hr from siRNA introduction, a soft agar medium and cells were mixed, 1.5.times.10.sup.3 cells were seeded again and, 8 days later, formed colonies were photographed using In Cell Analyzer 1000 (GE Healthcare Bio-Sciences Corp.). As a result, the colony formability was suppressed by introducing siRNA 12R#506, 13R#9443 into colorectal cancer cell line SW480, and siRNA 12R#506 into colorectal cancer-derived lymph node metastasis cell line SW620 (FIG. 11).

[0101] From the above, a suppressive effect of the suppression of expression of lncRNA12R and lncRNA13R on the colony formability of cancer cells was confirmed.

Example 7

Suppressive Effect on Migratory Ability of Cancer Cells by Suppression of Expression of lncRNA12R

[0102] siRNA for lncRNA12R (custom synthesized siRNA, GeneDesign Inc.) was introduced into colorectal cancer cell line SW480 by a method similar to that in Example 6. The target sequences of siRNA used are shown in Table 4 (SEQ ID NOs: 42-44). The control siRNA used was AllStars Negative Control siRNA (QUIAGEN, 1027281). After 24 hr from siRNA introduction, the cells were suspended in a serum-free medium, and 4.times.10.sup.4 cells were seeded on an upper well of xCELLigence Real Time Cell Analyzer DP (Roche Diagnostics) CIM plate 16. The wells were connected by filling the lower wells with a medium containing serum, and the migratory ability was evaluated using the serum as an attractant. As a result, the migratory ability of the colorectal cancer cell line was suppressed by decreasing the expression of lncRNA12R by siRNA introduction (FIG. 12).

[0103] From the above, a suppressive effect of the suppression of expression of lncRNA12R on the migratory ability of cancer cells was confirmed.

INDUSTRIAL APPLICABILITY

[0104] According to the present invention, novel lncRNA induced by .beta.-catenin can be provided. By screening for a nucleic acid or substance that suppresses expression of the lncRNA, cancer can be diagnosed or treated.

[0105] This application is based on a U.S. provisional patent application No. 61/727,185 filed on Nov. 16, 2012, the contents of which are incorporated in full herein by reference.

Sequence CWU 1

1

5014395RNAHomo sapiens 1aaaauaagca gaugaacaag auaagcguuc cccugggacc ugaaagacgc agaagaacaa 60guaggaggaa cauucggagg agaagaccua gcugcagcug gguccuggca aaguuaucgg 120guucugcucc cucugccugg gugagguacu ggcaaaguuc uccgguucug cgcccucugc 180ccagguuuga ccaaggagcu uauguuuuua agucauggaa uaaaacaugg auuacuauug 240uggguugaac ugcauccccc aaaaagauca guggaggucc uagaaacaca ggacuucaga 300augugacugu gucugaagac aaggucauug cagauguaau uguuaagaug aaaucauacu 360ggagcaggcu gggcccacuc caguacgacc gaugucauca uaagagaaga gacacagaga 420cuccacgugg agacagaggc ggagauggga gcaauguggc cacaaaccca ggguugccac 480aaccagcaga aacuaggagg aggcgaggca ggagccuccc cugcgccucc agagagagcc 540uggcccugcc aauaccguga uuucggacuu cuuuuaaccu ccagaauugu gcaagaauaa 600auguugcuug uuuugagcca cccagcuugu gguccucagu uacaacaguc ccaggaaacu 660aauacaucua guaaauaaaa ugagagcggu uucucugcau gaacugaaau gauggcgggc 720ucugcaggga caguucgcag acaucugcaa acaaauacug uccaaaccgu gguaaacagc 780cgucuuuuau uucggcgaaa gccuuugggc caguuuucgu auguuguugg aagcacuaaa 840ucucucgcug gcagagaucu gcaagcagcu acaagccagc ggcucaccug cagcaaaacg 900ccuggaggca gguccaugca augcccacgu cuugcauguc auugugcagu uaaacagcuc 960cugaaccaga gagcagcugc gcccagacag cuucccgggu gguaagaacu guauuugacc 1020uccuggcagc acaaacgacu gaauaacaau uaaacaaaac aggacagucu ccguguuuca 1080aaaugcgcau uuaaaccuaa aagaaacacg guguguuuac uuucugagcc uggccuuccc 1140ugggugcaca gugagccacu ucugaaagcg uaugggcaca cccgcuacag aaaccagcuu 1200acacuggcuc gguugccagu ccuggggcau uucagaagaa uugagucaga aagguguuuu 1260cuguggguga uucaaaggcu ccaggucucc agaaauuugu ugcaugaaau ggagaauaag 1320uaggcucggg cucggacuug gccgcgugca gcuucagggg ugaagcugcu uggaggccag 1380gggccagccc cagugcuugg augcuggggu gcagauccgg gaaugggaug auagccaggu 1440ggaaaggggg agguggcucc ugggucuugg agaagagggu gagaauauaa ccaaagauuu 1500gucugaaagc cagacagugg agagucagcu uggcugugaa ucauaccuag uuugagcaua 1560aagaugagaa gugaaaacag agauggggag guaaaaaagg agggggaggu gaacagagag 1620gcuuaggucc ccaucgauaa caguagcuaa ugacacguga acacgggauc ucuuugcuug 1680cuuuucuuuu uuuuuuuuuu uuuaagacag ggucuugcuc ugucaccaaa gcuggagugc 1740aguggcacaa ucauggcuca cugcagccuc aaccucccgg guuccaguga uccacccauc 1800ucagccucca gaguagcugg gacuacaggg gugcaccacc auaccuggcu auuuuuagua 1860uuuuuuguag agacggguuu uuuugccaug uugcccaggc uggucucgaa cuccuggguu 1920uaagugaucu gccugccuca gccucccaaa gugcuggggg auuacaggug ugagccacug 1980caucuggcca agggauaucu uuugagaucu ucuugcccca gagcuuaauu ucagaaucca 2040gcgugauugu uaaagaagaa aauaaacggg cuuuuucuau uuuaccugga gcaugucacc 2100aggacaauuu ucauccaaag accuaguuca auggggcucc uuccccaagc uccccacaca 2160cgcuccggga aucgauuuuu uuuacaguug ucugaagugc aagucaagcu uuugcacaca 2220cacucucucu cuuucucuuu uucucugucu uaaauugcca gaaauguaca auuuuccuaa 2280uggagaguuu auuucaggcu caucaagaua aaauaaauuc cgcuggugug cagccggcca 2340ggcgcagggc agagcggcgg caagcggccc gcgggcagag ggggcagcga ggguccaugc 2400ucagcgucug aacguuacau uggcaucugg ggaggggggg ggcuccaugu guggucacgu 2460gaacuccgag aacgaaccug gcugagcaca gucgaccuug ucacugucau gacccaaggu 2520guccucugug acuggacaug gggcggggug cguuacguag augacucguu aagcucuagu 2580ggcuaacuca gugcguccau gaaggcugug cggagaugcg gccggcagaa ggcaaacaua 2640gaugacgcug gggauaucgg uguaaauacg gguauggcca guuggucgau acagaagggu 2700uuguuugaag gccuucgcuc acacgauugu ggcugcuggc aaauccaaaa ucuauaaggc 2760aggcuggcgg cuggagccuc aggcaggauu ucuacgaggc agaauuucuc cuccuucggg 2820aaaccugcuu ccccucggaa ggccuucugu gggcugcgug augugcuccc acaugcucag 2880gggcaagcuc cuuuauuggc uguaggcauc ggccacaucc ccaaaacacc ugcccagcaa 2940cccugagaug acugcuuggg uucgucucca gguacgcuaa gccugcccac auaaaacuga 3000cugccacaca cugacguucu ccggugagag augggagacu cagagaggcc acuuccuuug 3060ccaggguugu agagcaaugg aagggcuuga guggucaggu cuuugggucu cauugccugu 3120gguucuaaac uagcagagug uggaaugccu cggcuuccac ugacccugug gccccggcag 3180ggccuccacc aucaggaccg ccgagcacgc ccuccugcca ggagcgacgu ccuccuuccu 3240gagaaguuuc ucgugggugg gagggauggg aaccggacuc uugacaccuc ccuggugccc 3300cagccccacc cucgcaaggc ggaccaccca gaagguucuu ccggccccuu uuccaaagcc 3360cuccugccuc acuuaaccca gcccagguua acugaugacu gugggaagag auguuuccag 3420cagcacacug ucuuguaauc caaggggccc uggaaaaagg gguuucgcag cggcacugug 3480gucucagagu ccaugcgaga ggaaacacau cugucccugu auuuuccgca gacacccccc 3540cucgccuccc ccacgucccc acaggcuguc auauuguuuc caguuguguu uaugguaaac 3600ucaggccaua acacgccucu gucguuguaa aagauggaaa gagucuuagg agagaaauuu 3660ucaucccagg ccuuucaagc ggcauuuucc cggugguaga ggugaauggg aaacaugaag 3720cagcugccug caggaacguu uuucccucug uggcaaggau aaacagugaa aggcguuugc 3780ugaagaugga aagagacacu gugcaaacca auaugcacag cuccugaggc cugugcuggg 3840ggccguggcu ugcugacguc ucuccaaaua cgcaagucag agaagggcug acucacaggu 3900cauggauugc aaaaaauaug gcacaagccu gacuucgaac uuucaaaggg acaaggacgu 3960gcacgccaca gccacagccc cagaccaggg uguaggccgu ggggcuccag cucccuucug 4020ggcaucacug cugugugucc uugggagagu gucuccgccu cucuggcacc ucccuucacu 4080cuggaaaccu guccaucagg ccaggggacu gggguggcgu gcggccuacc uccucccacc 4140uuccgagccc aaccccaaaa cuggauaagc agucagcuug cacucugaac ccagaacuga 4200aacgaggauu aagcuucgcu uugugcgugc cacaaaccag acaccacauc caaccuccgg 4260cucuagggcc aggaacucca aucaccaagc auuuuuggaa aaccaaauca aagcuagaug 4320gcuuuucuaa cauguuauau uguauuaaag auugaaaaug acauugagaa guaaaaauaa 4380auuggaaaua acugg 439521868RNAHomo sapiens 2gacccccagc ccugcucccu gaaucaccac cccucgagau gacacgcagu gaccaauuuc 60cucuuaaaac ucccuucugu ucaaaaaccc uaugauccau gcacccucug ucuaauccuc 120ugcgaugggg ccagucugca gauccgucug ggcgggcugc gguagcauuc uccaccugcc 180aacacucagu ugcuggugag uaaccagcau acggacucuc acuuccuaga ugacgccuug 240cuguguugcc cagggugguc ucuaauuccu ggccuuuagc aauucucccg ccuuggccuc 300cuaaagcacu gggguuacag gcaugaacca cugugcccag ccugcaugau guaaucucca 360aaggcaggag agagaguggu cucacaacgg aagggcacca gccacugaga aguccuaagg 420ccguguuuga guucuggcuc aucuuuuuug cuaauuugcu cuuaugcaua ucacccaacc 480ucgcuaagcc aguuucauca ucagcgagaa cagcacacug acaugcaggg ccagcucagg 540cgcuaccaca agcuacacau ccguccauuc guuuaaucuu cacagcagcc cuggggucac 600ccaggcaugg aaugcacagc ucugccagac agaaagcgcu uuggaugccu gagaaacaac 660agcuuguccg ggcuacugau gcgaagagag gccaugguuu ccuuuuucuc 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540ucgagaugac acgcaggacc aauuuccucu uaaaacuccc uucuguucaa aaacccuaug 600auccaugcac ccucugucua auccucugcg auggggccag ucugcagauc cgucugggcg 660ggcugcggua gcauucucca ccugccaaca cucaguugcu ggugaguaac cagcauacgg 720acucucacuu ccuggucacc caggcaugga augcacagcu cugccagaca gaaagcgcuu 780uggaugccug agaaacaaca gcuuguccgg gcuacugaug cgaagagagg ccaugguuuc 840cuuuuucucu gcucugaaug gcagccuuga cgucacaaca gcuaggaacc acuggaggga 900caaauaacaa ggcgcaagcc agaagcgccc ugcucugucg caggggcagg gccauuuuca 960uccaguucug augucuucug uggccgcugc gagucggcgg gaguagagac aaaugacugg 1020agcuuuaggc guaaaggcgg ucucucucua ggcugaucaa acagcccuuu gcccagugcu 1080aauugccuuc acggaaccug gauaaacuac aguucccgaa uuaaacuugu uucugaugaa 1140cuagacuucc cagggaaugg guguagugau uuugcugaug guucagacau cggcacuuuc 1200ccugaagggc ucaacuuccu guguuuaaaa gcagaccuaa caggggcugg cgcauaagca 1260ucccgggaaa uacaagaagc ucaugaaagc aggcagccuu ugcaagagac cugacuuauu 1320uucuaggaga aaaacauccu uuuagggauu uuauaauuua aguuuaagca auuaaacaug 1380ugcaucagua cccaacugca gguguuugaa caaaugaggg gaaaacgcuc agaggcugcc 1440aggcuuaacu caccauuauc uaaaaugaau ugucugugua agucaucaca gcaguuugaa 1500aagcaugauc uuucauguuu caaccucaca ucaaaauucu aaauuauauu uagcuaugug 1560agugucagau cauuuguuuc cauuaucaau gcgauguugg gcaauuugca gacaggaucu 1620gaaagcauca uccaugacuu ucauggaaca gaaaagagcu uucuguugcc acagauuugc 1680ccuaaguuca guccucugcc uuuggagcac ugacagcugu caccaaaccc aaaccccagu 1740cugaacccau agugcucaag guacuuuggg aaagcuaauu caggaaaacc acaggcugga 1800gggguugucu uugaggugug uaugugugug uguguguaug cacauuuguu ggcagugugu 1860ggacugagca caacauauag agaggcagug uucucaggac uucugugcuc cuauuuggaa 1920aaauucggca gaagaaacaa cagcucugag acacucagcc ccuuucauca gcucuuucuu 1980ugcuuaauua aauacacagu ucccccc 200741636RNAHomo sapiens 4gacccccagc ccugcucccu gaaucaccac cccucgagau gacacgcagu gaccaauuuc 60cucuuaaaac ucccuucugu ucaaaaaccc uaugauccau gcacccucug ucuaauccuc 120ugcgaugggg ccagucugca gauccgucug ggcgggcugc gguagcauuc uccaccugcc 180aacacucagu ugcuggugag uaaccagcau acggacucuc acuuccuaga 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agacaggauc ugaaagcauc auccaugacu uucauggaac agaaaagagc 1200uuucuguugc cacagauuug cccuaaguuc aguccucugc cuuuggagca cugacagcug 1260ucaccaaacc caaaccccag ucugaaccca uagugcucaa gguacuuugg gaaagcuaau 1320ucaggaaaac cacaggcugg agggguuguc uuugaggugu guaugugugu guguguguau 1380gcacauuugu uggcagugug uggacugagc acaacauaua gagaggcagu guucucagga 1440cuucugugcu ccuauuugga aaaauucggc agaagaaaca acagcucuga gacacucagc 1500cccuuucauc agcucuuucu uugcuuaauu aaauacacag uucccccc 154861839RNAHomo sapiens 6caggagagcc guccacgccu gcugugggag gaagacgcuu uccugaggca ggggccaggc 60agcuucuguu ggcgccugga acagcuuccg cucaucgcuu cuggcggcac acacugcgga 120ggugagacug caaaugccgc ccgccccacg uggugcaggc ugagugcucu gguguuuguc 180caagcuguuc caagcccagg aggucggacu cucaccgucg ucuuggugau ggcaacgcug 240uguccugccc caccucgugg cugcccccac cuguaccggu gagaccugag gguacgggug 300ggguggaucc ugccauuccc aagggcuaag uccugagacc cuuuugaaac cccguuugaa 360aaggugacaa uagcguaugg cuucccgcac caagugcaca caguacacua gcgacaggca 420caaaggcaac augaaacggg 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gcugacucau cgugacggcg 1320aguggggcuc cagcuccgcg gcauuucaua gacagcgcgg ucacauuccu uuccaacagu 1380cgcucuggcc ucgaugucua aggcuccgug ggcagccggc cuguggauga ggcggcggaa 1440accacauccu cuucaucauc cucucacgag gaaggacacu gacagcuucg gagaaggcug 1500cccagugucu gcgggugccc uugggagaug gccuugggac acggugccug ugccugugug 1560uguacaccac gugugaacgc caacugggaa cacggccccu ucguaggcaa acccaggccu 1620ccuggaaguc acaaguugau agcuguacuc gccccuuuug gaagacgcac gcccaaggca 1680cccgugugug cacacguauc cgugugugga ccucugucca cacgugugug uuuugaaaag 1740ccuuucucac cacauguuag gaucacaagu guucaaaauc uaggcacacu uuucagaagu 1800uauuucugga aaaaauguug aaucucauaa cagcaauaa 183971362RNAHomo sapiens 7caggagagcc guccacgccu gcugugggag gaagacgcuu uccugaggca ggggccaggc 60agcuucuguu ggcgccugga acagcuuccg cucaucgcuu cuggcggcac acacugcgga 120ggugagacug caaaugccgc ccgccccacg uggugcaggc ugagugcucu gguguuuguc 180caagcuguuc caagcccagg aggucggacu cucaccgucg ucuuggugau ggcaacgcug 240uguccugccc caccucgugg cugcccccac cuguaccggu gagaccugag gguacgggug 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gauagcugua cucgccccuu uuggaagacg cacgcccaag 1200gcacccgugu gugcacacgu auccgugugu ggaccucugu ccacacgugu guguuuugaa 1260aagccuuucu caccacaugu uaggaucaca aguguucaaa aucuaggcac acuuuucaga 1320aguuauuucu ggaaaaaaug uugaaucuca uaacagcaau aa 1362811431RNAHomo sapiens 8cgaggaggcc caggcgguga

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acuccuuuau ucugaggccc 3060cagaauauuc ucauccacca cguacuuuca cguggagaug acugacuuca ucuuugacaa 3120uggcaguucc cuaaccuuga uccagcacgg gagcaggaau uauggcgaaa auggccaccc 3180aaacugcacc cagugggaaa acagcauuaa cucagcuuuu aaaaaagugu caacuuggaa 3240aauccaagac cuagaucuga ugcuuaggga cccacaaugc caggcagcag ucugggagau 3300gucacuucug gagcuucuaa ugagaugcaa aucaccuagu gaacuacugg ggagcuggga 3360aacaaugucc uggguaaaag cagauaaaaa uggaaugaaa gaauuucuuu gaagauugga 3420acgacauuuu aagugcuugc ggauauggga caccagauag uguugguuuu acuaagcuaa 3480uugugacggg gucuuugauu cccugcagca ggggacccug gggcacucgu cuccagcucu 3540gccucacucu uugaggagcu aguuccaguu cuacugugag ugugcaaggg gcuggucagc

3600uguagcaaaa ccagcacugg acauggggga ucagaagacc ccggcacaca uaguucaagu 3660ugugacacau auugguaugu gaccuuaagu gaaucccuua ccccucugcu gccauguuuu 3720auguguaaaa ugauaaagag agggguggac ugagguagua auuuuuaaug gagaacauug 3780guguggcaaa uuacacaugu ucuggccuga agauucugag cugcucuccu uggagucaca 3840uucuuuccca gugugugaac aucugugugc agugagagac augccugaug gggaucuguu 3900gccugaagcc agugugaagg caggaaaagg cuuguuggaa uuuaaauacg accaaucaaa 3960auguguuuag gcuucaaagg aaaaaguucu ccauaaauac accagaauuu cauucuaaca 4020ugauucauuc auucaaagag cacagcugca caaggggaag acagcugcca caugguaacg 4080caguccugua aagaguccca uguggugaga gacgugguug ggagugagcu uggaagugga 4140uccccaaccc ucguccccaa acugagacuu cacaugagac ugcagcucug gccaacagcu 4200ucacuguaac cucacaacag accuugagcc acaagcaccc agcuaag 4247101828RNAHomo sapiens 10cagcgaccag aacauucauu ccagggcugc ucugcagcug cccaggcagc uccgugggug 60gccacucugc uaacguggga gcacacgugg cuuccaucug augagcaguc ucagggaagc 120ugggggcuuc agacaccaaa ugucuauuuc ccuccuugau uugagacucu uuuggagcuc 180uuggagacuu ccagcagaaa ccugagcugc cggcugccaa gaaucagcgg uggauuucuu 240gaccugcucu uaauaccaau ugaauaaccc cuuugaaaac guucacauac augggguaca 300aggugguacc uuugugcaug agacuguucu ggagacggcu uaucacccag caaaucagug 360uuggccaucu gggacucagc gacccuuucu acgaggcuau ggugaagucu cacucuguug 420cccaggcugg agugcagugg cacgaucucg gcucgcugca accuccaccu cccagguuca 480agcgauccuu cuguuucagc cucuccagug gcugguauua caggaacaca ccaccaugcc 540uggcuaaugc uucucuuucu auaaaugaag acgugaggcc guguaagcuc caagagagca 600gggaucuugu uugucuuggu caccgugaua uuucagcugc ugacccagug cuugaagcau 660aaagagaaac ugaggcccau aaaauugaau ggcucaucuc agaucaagug gccagaucaa 720ugaagagaag uguccuuagg uccggcugcu ggugugaagu augcucugga ggucugacau 780ccacucuccc ucagacuuuc uaauacggca ggaauuccgu ccaugaacuu uauaauaaac 840uggagcuaaa ucugucagaa aauggaagaa aucuggauag cauuucagga gcacuggcaa 900augccuacuc cuuacuuccu aaucccaaac ugucacacug uggcugcaca ugugcccaag 960cccuuguaua cucaagcuag aguugccaga ugaaauggag gacauggcug ggugcggugg 1020cucagcucgg agcaguggcu cacgccugua aucccagcac uuugggaggc cgaggugggc 1080ugauggccug aggucaggag uucaaaacca gcguggccaa caagaugugc caguucuggu 1140aaauuuccua gcaagcuuga aggaagugaa ggacaacugc aaggaagggc aggauggagc 1200augcagccca cguauucccc agcuuggugg ggcagaaugc guucuuggcu ccugaggaau 1260gggcaggcaa cgcacagggg uccugggaag aaagggagag aauauccugg gagagccaua 1320gacccuggca cccuccugug guccuucauc aggauaaauu ucuaaaagaa gaauuacugg 1380ccaaaggauu ccucuucagu uggaaacagc agcaaaguuc acaggucgug aguggaugua 1440aaguggacgg aacagguugu ugccagucua uuggaguagg augguagaug agcagucccg 1500uuggcuaaca gcuuguugga auuuaaauac gaccaaucaa aauguguuua ggcuucaaag 1560gaaaaaguuc uccauaaaua caccagaauu ucauucuaac augauucauu cauucaaaga 1620gcacagcugc acaaggggaa gacagcugcc acaugguaac gcaguccugu aaagaguccc 1680auguggugag agacgugguu gggagugagc uuggaagugg auccccaacc cucgucccca 1740aacugagacu ucacaugaga cugcagcucu ggccaacagc uucacuguaa ccucacaaca 1800gaccuugagc cacaagcacc cagcuaag 182811730RNAHomo sapiens 11cggcggcugg cacagcggag cugcucucca agcagcgggg uucccaggcu gggaaguuug 60cauugccguu ucuuugcggg cgggcggcga gcgccgacug caugccaccu gcgagaggaa 120gaggccggac cccaagguuu uagccugugc ggcaggagga auagcucagu ugcugacaaa 180agcaggagaa caaggaaaag agacagcugg gaguuaagca gaaggacuga auucagcgug 240ggcuguugaa ucuaagauuu uggcuggcug cucgugaaga aacgccugca gaaagcugua 300aaugccggca guggcaguga gugugaugga caaggcuaaa gagaagacuc augaacuuuc 360ggcacaagaa accaaaucuu uacugagugu gguggaagaa ugcccaggug agcacaggca 420cagugccagg ugcugcagag gaccugagac aaagagucac ugcgcccuca gagaguuuag 480aauccagcac ugaggaaaag agaggucaug gggagcacag uccuccugac aucuuaaucu 540aucugccaac gcuacaugcc gucaagccaa ggaagaauuu ccuucucacu guugcuucuc 600ugaccaagga agacauaagc acaaccaauc accagacuga ugaaauuccu uccaguuuca 660gaaaagauua ucaccaaucc cuacauuaua aaauucauac uaauaaagca caaacauuga 720auucuaacau 73012337RNAHomo sapiens 12cggcggcugg cacagcggag cugcucucca agcagcgggg uucccaggcu gggaaguuug 60cauugccguu ucuuugcggg cgggcggcga gcgccgacug caugccaccu gcgagaggaa 120gaggccgucc uccugacauc uuaaucuauc ugccaacgcu acaugccguc aagccaagga 180agaauuuccu ucucacuguu gcuucucuga ccaaggaaga cauaagcaca accaaucacc 240agacugauga aauuccuucc aguuucagaa aagauuauca ccaaucccua cauuauaaaa 300uucauacuaa uaaagcacaa acauugaauu cuaacau 33713570RNAHomo sapiens 13cggcggcugg cacagcggag cugcucucca agcagcgggg uucccaggcu gggaaguuug 60cauugccguu ucuuugcggg cgggcggcga gcgccgacuc augccaccug cgagaggaag 120aggccggacc ccaagguuuu agccugugcg gcaggaggaa uagcucaguu gcugacaaaa 180gcaggagaac aaggaaaaga gacagcuggg aguuaagcag aaggacugaa uucagcgugg 240gcuguugaau cuaagauuuu ggcuggcugc ucgugaagaa acgccugcag aaagcuguaa 300augccggcag uggcagugag ugugauggac aaggcuaaag agaagacuca ugaacuuucg 360uccuccugac aucuuaaucu aucugccaac gcuacaugcc gucaagccaa ggaagaauuu 420ccuucucacu guugcuucuc ugaccaagga agacauaagc acaaccaauc accagacuga 480ugaaauuccu uccaguuuca gaaaagauua ucaccaaucc cuacauuaua aaauucauac 540uaauaaagca caaacauuga auucuaacau 57014818RNAHomo sapiens 14caggcuggag ugcaauggcg ugaucucggc ucacugcaac cuccgcuucc cagguuccag 60cgauucuccu gccucagccu cccaaguagc ugggauuaca ggugugcacc accaugcucg 120gaaaaaugga uggacauguu uuacugccug aacgcuggug ccaguuaggc caacagucau 180guggcaaugg cuaugaauug caagcauugc ugauuguuau cugcugcuac ugccuuugag 240cuggagcgga acagaucaac augggccaaa caagagccuc uuuggagauu ucucuacugc 300uucaagcaca cagauuccaa guuuagaagc ucaagagaag guugaaaaua aaauacauuu 360aguuuuuguc aucuaccugg gauuacuuca cuauuggaaa agaauaucac aagauaauau 420aaauaacaaa uuaccauaaa ccuauucucg guggauccuu aaccuguaca aaugagacca 480gguguuaauu ugaugacugu cagagcugga agggcacuaa ggcauuaucu aguccaauga 540augaugguca aacuuaaugu ggcacagcag aacucuuuuu ucagaaagac ucguauucag 600augccugaua aaaacagaaa uucucuagcu gaagcagggg uuagggacuu gagguuuuau 660guaugugaaa ugugugugug uguauguaua aauguauaug ugggggggug uauguguaua 720uaugugugug aguauguaua uauguauggc auucugugug ccaggcucug ugguaagccc 780uggacuuaga gcaacaaaua aaggaagaca uggccuca 81815798RNAHomo sapiens 15caggcuggag ugcaauggcg ugaucucggc ucacugcaac cuccgcuucc cagguuccag 60cgauucuccu gccucagccu cccaaguagc ugggauuaca gaaaaaugga uggacauguu 120uuacugccug aacgcuggug ccaguuaggc caacagucau guggcaaugg cuaugaauug 180caagcauugc ugauuguuau cugcugcuac ugccuuugag cuggagcgga acagaucaac 240augggccaaa caagagccuc uuuggagauu ucucuacugc uucaagcaca cagauuccaa 300guuuagaagc ucaagagaag guugaaaaua aaauacauuu aguuuuuguc aucuaccugg 360gauuacuuca cuauuggaaa agaauaucac aagauaauau aaauaacaaa uuaccauaaa 420ccuauucucg guggauccuu aaccuguaca aaugagacca gguguuaauu ugaugacugu 480cagagcugga agggcacuaa ggcauuaucu aguccaauga augaugguca aacuuaaugu 540ggcacagcag aacucuuuuu ucagaaagac ucguauucag augccugaua aaaacagaaa 600uucucuagcu gaagcagggg uuagggacuu gagguuuuau guaugugaaa ugugugugug 660uguauguaua aauguauaug ugggggggug uauguguaua uaugugugug aguauguaua 720uauguauggc auucugugug ccaggcucug ugguaagccc uggacuuaga gcaacaaaua 780aaggaagaca uggccuca 7981620DNAArtificial SequenceSynthetically generated oligonucleotide 16ctgggtggct cctctcaacc 201720DNAArtificial SequenceSynthetically generated oligonucleotide 17ccaaagggac ccacatcgac 201820DNAArtificial SequenceSynthetically generated oligonucleotide 18gctgatccca ggccctacct 201920DNAArtificial SequenceSynthetically generated oligonucleotide 19gaatgcctcc cggtccttct 202020DNAArtificial SequenceSynthetically generated oligonucleotide 20cccaaccacg tctctcacca 202121DNAArtificial SequenceSynthetically generated oligonucleotide 21ttcaaagagc acagctgcac a 212220DNAArtificial SequenceSynthetically generated oligonucleotide 22gattcaacag cccacgctga 202320DNAArtificial SequenceSynthetically generated oligonucleotide 23atgccacctg cgagaggaag 202425RNAArtificial SequenceSynthetically generated oligonucleotide 24uucuggaugu gguucagugg acugg 252525RNAArtificial SequenceSynthetically generated oligonucleotide 25auaggagcga augugaacac uguuc 252621DNAArtificial SequenceSynthetically generated oligonucleotide 26gcaaatcagt gttggccatc t 212721DNAArtificial SequenceSynthetically generated oligonucleotide 27ggtgtctaca tggcagcata a 212820DNAArtificial SequenceSynthetically generated oligonucleotide 28gacggaggtt gagatgaagc 202920DNAArtificial SequenceSynthetically generated oligonucleotide 29attcggggct ctgtagtcct 203020DNAArtificial SequenceSynthetically generated oligonucleotide 30tcccggaggt gctctcaatc 203120DNAArtificial SequenceSynthetically generated oligonucleotide 31gggctccctc tctccactcc 203220DNAArtificial SequenceSynthetically generated oligonucleotide 32ttgcccaggt ggcctactct 203325DNAArtificial SequenceSynthetically generated oligonucleotide 33ccttctcaga caaatgcctc taagt 253425DNAArtificial SequenceSynthetically generated oligonucleotide 34agaaggagat cactgccctg gcacc 253525DNAArtificial SequenceSynthetically generated oligonucleotide 35cctgcttgct gatccacatc tgctg 253625DNAArtificial SequenceSynthetically generated oligonucleotide 36caagcactac caccagcact gttac 253725DNAArtificial SequenceSynthetically generated oligonucleotide 37gcaatcagga ggcacaggac ataat 25387058RNAHomo sapiens 38cagcgaccag aacauucauu ccagggcugc ucugcagcug cccaggcagc uccgugggug 60gccacucugc uaacguggga gcacacgugg cuuccaucug augagcaguc ucagggaagc 120ugggggcuuc agacaccaaa ugucuauuuc ccuccuugau uugagacucu uuuggagcuc 180uuggagacuu ccagcagaaa ccugagcugc cggcugccaa gaaucagcgg uggauuucuu 240gaccugcucu uaauaccaau ugaauaaccc cuuugaaaac guucacauac augggguaca 300aggugguacc uuugugcaug agacuguucu ggagacggcu uaucacccag caaaucagug 360uuggccaucu gggacucagc gacccuuucu acgaggcuau ggugaagucu cacucuguug 420cccaggcugg agugcagugg cacgaucucg gcucgcugca accuccaccu cccagguuca 480agcgauccuu cuguuucagc cucuccagug gcugguauua caggaacaca ccaccaugcc 540uggcuaaugc uucucuuucu auaaaugaag acgugaggcc guguaagcuc caagagagca 600gggaucuugu uugucuuggu caccgugaua uuucagcugc ugacccagug cuugaagcau 660aaagagaaac ugaggcccau aaaauugaau ggcucaucuc agaucaagug gccagaucaa 720ugaagagaag uguccuuagg uccggcugcu ggugugaagu augcucugga ggucugacau 780ccacucuccc ucagacuuuc uaauacggca ggaauuccgu ccaugaacuu uauaauaaac 840uggagcuaaa ucugucagaa aauggaagaa aucuggauag cauuucagga gcacuggcaa 900augccuacuc cuuacuuccu aaucccaaac ugucacacug uggcugcaca ugugcccaag 960cccuuguaua cucaagcuag aguugccaga ugaaauggag gacauggcug ggugcggugg 1020cucagcucgg agcaguggcu cacgccugua aucccagcac uuugggaggc cgaggugggc 1080ugauggccug aggucaggag uucaaaacca gcguggccaa caagaugugc caguucuggu 1140aaauuuccua gcaagcuuga aggaagugaa ggacaacugc aaggaagggc aggauggagc 1200augcagccca cguauucccc agcuuggugg ggcagaaugc guucuuggcu ccugaggaau 1260gggcaggcaa cgcacagggg uccugggaag aaagggagag aauauccugg gagagccaua 1320gacccuggca cccuccugug guccuucauc aggauaaauu ucuaaaagaa gaauuacugg 1380ccaaagaaag uucacagguc gugaguggau guaaagugga cggaacaggu uguugccagu 1440cuauuggagu aggaugguag augagcaguc ccguuggcua acaggugugg guaugccugu 1500uuuaaaaauu agcauguugu aggggaauau uucucaaacu uuugucacgu aucuaccucu 1560uaggcauuuu uuacuuuauu caccuguacu acuauuuaau auuuuuaaaa uucaacugau 1620uuuuuuuuuu gcuuaaauac augucuuuaa aacuggaacu uuauucgcca cuguaaaugg 1680aaaaccagug ucauuugcca uauauagaag ugaacuauau aguaaauacg gugaaaguga 1740aaugguauca ucacacuugu gcuagauucc auuuccuaua gaagguucug gguuucuuaa 1800aaggcuuguu aaaaagagag augaguaaau gugagaggaa uuuaagacau acuagcacca 1860uuaagacuuu cuccuuaaag uaaucuggag gauuuaaauu gagaauugaa aaaaguaacu 1920uuauuuuaca uaagaaauua uguaaaagaa uuauguuauu uaaugccaca uccauacguc 1980aucaagaguc aacuugguga ccacuagugg cccauguccc acacuuugag aaacgugugu 2040ugggguggga aucugaaguc agaaaaacug gaguaugaua accaccucag cacuuauuag 2100aggccuucac uugggaauga ugacccuucc uuguaggguu guagugagaa ugacagauaa 2160uauaugaaaa gauaaaacau ggugccagag gcauuagcag gugcugcgaa ggggcuguug 2220uauuucuugu uauacuggag ugguucucca cccuggaugc auauuagaau caucugaagg 2280gcuuuuuaaa aauacagaua ucaugaccuc accccuggag auccuaauuu aauuggucag 2340ggguaggguu cuggcauugu uacuuguuua aaacaaaguu ccuccuccuu cccagugauu 2400uuaauuugua gccaguguug gaaaaaccau ggacuuaacc cuuuccuaag agcuuagauc 2460aauucugcag auuagcuauc ugccauuuug aaaagguggc auaagcucag ggaaguauuc 2520acuggacaaa aggaauucug gauggcggaa gcucuaggca ccaucaggca cuugcuuugu 2580gcuggaagcu gcaucaaaug gcuugagccc aaaguagaca uaagggcucc uuauuucccu 2640ggacacuggg aaaaucauuu cucuuauucc aagagaacaa uuuugcugac cauggaaaua 2700cuaucucugg uuuccagagg uacagugcug uucagugcuc uucuggaggu uguaguauga 2760agaaaugaca aagccaaaaa ggcauucuga ccuagggaga cuaucuuuaa agcaaaauau 2820aaauguaggg caaaaacucu gcggucucag gaggauugga uccaggggaa aauguuuaaa 2880aggcaaacgu uuagaaucaa uuauacagcu ucagcaaugg uuugcuauug ucuugcuguc 2940uuuuuguuuu gcuuugugua guguucagaa uaucugcauc auguagcauc uuucuauuuu 3000uaggagucuu uaaacuccuu uauucugagg ccccagaaua uucucaucca ccacguacuu 3060ucacguggag augacugacu ucaucuuuga caauggcagu ucccuaaccu ugauccagca 3120cgggagcagg aauuauggcg aaaauggcca cccaaacugc acccaguggg aaaacagcau 3180uaacucagcu uuuaaaaaag ugucaacuug gaaaauccaa gaccuagauc ugaugcuuag 3240ggacccacaa ugccaggcag cagucuggga gaugucacuu cuggagcuuc uaaugagaug 3300caaaucaccu agugaacuac uggggagcug ggaaacaaug uccuggguaa aagcagauaa 3360aaauggaaug aaagaauuuc uuugaagauu ggaacgacau uuuaagugcu ugcggauaug 3420ggacaccaga uaguguuggu uuuacuaagc uaauugugac ggggucuuug auucccugca 3480gcaggggacc cuggggcacu cgucuccagc ucugccucac ucuuugagga gcuaguucca 3540guucuacugu gagugugcaa ggggcugguc agcuguagca aaaccagcac uggacauggg 3600ggaucagaag accccggcac acauaguuca aguugugaca cauauuggua ugugaccuua 3660agugaauccc uuaccccucu gcugccaugu uuuaugugua aaaugauaaa gagaggggug 3720gacugaggua guaauuuuua auggagaaca uugguguggc aaauuacaca uguucuggcc 3780ugaagauucu gagcugcucu ccuuggaguc acauucuuuc ccagugugug aacaucugug 3840ugcagugaga gacaugccug auggggaucu guugccugaa gccaguguga aggcaggaaa 3900aggguaagaa ccauuagccc agaggcccuu uaaagucccu uccaacuuua agaugcugua 3960acuccagagu aaucgccagu uaaccucuug gagccucauc ugugaaacug acauaaaugc 4020uuuugcuuuu cagcuuguug gaauuuaaau acgaccaauc aaaauguguu uaggcuucaa 4080aggaaaaagu ucuccauaaa uacaccagaa uuucauucua acaugauuca uucauucaaa 4140gagcacagcu gcacaaggua gguuccccug aaccacuuuc ugggucauuu gguuacugau 4200gggcuaaagg acaucauuaa aaccucaccu cagccuuugc ccagcuguua gcaaaaccug 4260caguguauag auuaauauug cacagcugua caaaucccca cccaggucca uaaauuauaa 4320aauauuuuua cacauagaga gggcagucau uaguaugaau gacaugauuu gggggagguu 4380auaucuacaa augucuggca ggugugugug ugugugagag agagagagag agagggagag 4440agagauugag uggaaauaga aaagaauguc aguaguagac caaaauaaaa ucacaaauau 4500aauuuuuuuc uugcauuuaa uuaauaagau guaaaaauga aaucaaugaa guguuagugg 4560ugagaaaugc aguugugauc uuucagucuu aaucuucaaa aaagccaaga aaauaguaag 4620uaucugagag aagcaaagau uaaauagaaa gguaugguuu gguuauuuuc cuaauuugug 4680ccgaauuuug gaacaaauuu cuuaaguaca uuacauuaua aaaucaauuu gguccaacua 4740uccaguaaac auuaagacgu uuguacaagu agggcagcac aaagcuuuca guucucugcu 4800cuaaucaaga auuuaaauuu caguucuuca gggucacaga gaacuaccaa auuucuuugc 4860cuuguuuuac aauccaauau gagauuagua aaaauccguu acggaaauaa ugcauaaaau 4920gaugacuucu caugcccucc cugaccugag gagguugcaa gagaucugaa uuucuccacu 4980ggacucaaga uuucucaaca aauuagcauc agcagcuucc ugcccccacc ccuuuuaaau 5040aucccuauac ucaggugggg cgugguggcu cacaccugua aucccagcac uuugggaggc 5100ugaggggggu ggaucacuug aggccaggag uuuaagacca gccuguccaa cauagcaaaa 5160cccugucucu acuaaaaaua caaaaaauua gccgggccug guggcguaug ccuguaaucc 5220cagcuacucg ggagggugag gcaggagaau cgcuugaacc cgggaggcag agguugcagu 5280gagccaagau caggccacug cacuccagcc uggacggcag agugauacuc caucuaaaaa 5340aaaaaaaaaa aaaacccuac acucugagug accuaccuga ucaguauagc uauaagcacc 5400uuccuauaug ucauaaaaaa caaaccaagc uuaaccaaaa aguaaauggu uacaguuguu 5460gcuaacaaag cugagaaaug gguaucuccu guguuauaca agugauauuu cagccuugac 5520aaggaaauua uugccuacac acacacacac acacacacac acacacacgc acaaaagcaa 5580augcuuuguc caugaaguuc gaccaaacua aaagauaguu ccagugcaau guaauuuuaa 5640guuuccaaau gaacauauuc caggaggcuc auaucagugg uccucagcuc uugaccccug 5700aaggaaacau ucuuucaggg acuugguugu cuugguuuag ucaaauaaaa uauuaacaau 5760cagaaaccug gcagcauuua ucugacaaua uagagaaaau cauauuaaca ugagcucuuc 5820acuggaauga ucuuggacau ccaugauggc accgggaaac gcgccaccag cucuggaagg 5880gugggaggcu cuggcugacu uggcaccuuc ccacuuccag cucucguggc cgcucauccu 5940gcaugagaug gggacccagc agagaggggu uaaauggguu gagaagccag uccagccagg 6000ggucauuagc aaucaaggac cagcauuaaa aggcagcagg agacuaaggu ucucugacag 6060gcuuggcucc aggcaccauc uggaaggaaa gaggcuguca aaguuggcuu aaaaaaaaaa 6120aaaaagaaau ucauggagau cuuuucuuuu caauaacaua acacaaacag uuauguuauu 6180uccagcgugg cuccuuccuu ggaaguuagg uuaucuucaa agugcucugu uuuugagagu 6240agggccaggc agucacauuu cuaggccugu uucuggccau gaugaaccag uuauuggcac 6300cuggguuggg accagcccaa gaccaagugu auggccaaca

aacucuuaua cuuugauagu 6360ggcgagagau cguaacacac augcuucaua auaagguaac uggaauaugu cagaucuaaa 6420guauggggca cagcucauau ccaauaaugc auuaaucaua uuccacacac uauauaauac 6480gaucugugac uaaaaagaaa aaaacagaca gcuuugcuua gaaaaccugu guucaagcug 6540aucaucuaag uugugauuuu ugacacaacu uaaauaauuc uaaaacaagc cuggguucac 6600uuucuaaggu aauuuguaca aggaaauguc agucaggggu guugcauauu acauacaugu 6660gguuacgaac uugguuuaca uuauugauua aauucauuuu cucuuucucu uuuuuagacc 6720uuuggauauc uccuccuccu uccccuuauc uauaaauaug uaagaaagaa aacauguuua 6780aaauacaaua uuuuauuucu uuugaucaca gauuagacuu aaagaacaga gaugcccuau 6840aaugugaucu uuaagagaua uuacaaagcu uccaaucuca cugugaggau cguuaauaua 6900uacauauauu uuauuauacu uuaaguucua ggguacaugu acacaaugug cagguuuguu 6960acauauguau acauguguug uguugguuug cugcacccau uaacuuguca uuuacauuag 7020guauaucucc uaaugcuauc ccucccccgc ucccccca 7058398139RNAHomo sapiens 39cagcgaccag aacauucauu ccagggcugc ucugcagcug cccaggcagc uccgugggug 60gccacucugc uaacguggga gcacacgugg cuuccaucug augagcaguc ucagggaagc 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ugcuuguaau cccagcacuu ugggaggugg agguggacgg aucacuugaa 4380gucaggaguu cgagacuagc cuggccaaca uggugaaauc ccaucucuac caaaaauaca 4440aaaaaauuag ccagaugugc uggugggugc cuauaauccc agcuacuugg gaggcucagg 4500caggagaauc guuugaaucc aggaggcggu gguugcagug agccgagauc augccacugc 4560acuccagccu gggcaacaga acgagacucc aucucgaaaa aaaaugguaa ggagagcggg 4620ugccgugacc uggagcaaag ggaggagucc ugggugacau cugccuccca uggcagggag 4680guccuccggu aaaccugcuu agacacgcac aguugcuuuc aacaguacug ccauggacac 4740gaaugaucuu uagguacaga caaggccucc uuacaagaga cauauguuag gaaaagguag 4800ugccaaaauu ccuuuauuaa guauauguuu uccuauuuag ucauuaaugu ucauguuuca 4860aaaugacccu guagcaagua ccacuugaug ugagaaggaa ucaaggcagg uucauggaua 4920aggcaugaac uuaaggucau ggcaggagcc ugcagaagcu cacaguacug uggcuuugua 4980cucuguggcu cugucaucua ucuuucuuuc uaggcacaag aaaccaaauc uuuacugagu 5040gugguggaag aaugcccagg ugagcacagg cacagugcca ggugcugcag aggaccugag 5100acaaagaguc acugcgcccu cagagaguuu agaauccagc acugaggaaa agagagguca 5160uggggagcac aggugggucc cacaaucaug ggaagaauac uguuggcugc aagggccugg 5220caacuaucua ugacucauga agaaacaggc ccagugaagu aacguggcuc cuugagauca 5280cagagugaaa gaacugaguc ucacauacau uauuugagac agguucucuc ucugucaccc 5340agguuggggu gcagugguac aaucucggcu cacugcaacc uccaucuuuu gggcucaagc 5400aauccuccca ccucagccuc ccuaguagcu aggaccacag gcaugugcca gcauauccgg 5460cuaacuuguu uuuuauuuuc uuguggagac agggucuccc uauguugcuc aagcuggucu 5520caaccuccug ggaucaagug auucucccgc cuuggccucc caaaauguug ggauuaugga 5580ugugagccac cacacccagc uucaucauuu uuccagugaa cauuuuucua gggaacauga 5640auauugaaag aaaagauucu ccauguacug uuacccaucu gugguggcau uuauuuccua 5700aaaagaaaug aaugugauaa aucuuucuuu uaggcugagc aauaauguuu cacauauaua 5760aaaucuugaa auuugaucug gauuauagca auaaaauaaa acaugcauua auauauagga 5820gaauuacuuu ggauacaaac ccaacaaaga uuuaaugaaa aacauuguca uauaucaaua 5880aaugcaaaua aagucugaac cccccccccc cauuuccacc ccucuaaguc uagcaccccu 5940agauggaggc ggggguuggc uaacuuaggc cggagagacg caugcuggug aggucauggg 6000uuugcucugg ucuguuggua guggucuuuu gggggccaca gccugcaugc ugucucccac 6060ccagugugcu uguuugacca uguggcuggu cgaccaugcu gcugcuacca aucacaacau 6120ggagucucau ggaauccucu caaugacucu auuuuauaga uggguaauuu gcccaagauc 6180ccauaucuug uucuuggaau ugagugcagg uaauguuacu ccagagggca accuuuuaac 6240caucagauua gagugccucc uugggugagu gcaaaucucu uucuauuauu ggaaaaacaa 6300uuaaacacgu augucagucu gugguggaau uauuaaauau gaagucuggg auauuuacug 6360gccacauuac agguuguuua uuauuugccu cauggugaaa augucggucc cacgugagau 6420guuuguuauc ugguuuuacc caaaagaagu augggucuug accucaagga uuauaguuca 6480gauccaugau gacuuuuucu uucacuucua gaguacucuu uucuuccccc uaccccuugc 6540cccaagccac cagggggcac acagaauugg ccauuuaccu uggaaaauuu aaggcaccaa 6600uuuuaaggau auagauaaau aucaguccag uaucuuuaga gguacagcug ggaauagacu 6660aacacuaaua ucagguaucu guccccauuu ccauuuaaaa gaucaucucu uuaaaauccu 6720uuaggacuga caagugucuc acccaugggc cuuuuggucu ucaggaggca augcccuuuu 6780uauuuguguu ucagugucau gguguaguuu caaguuggau cuguccucuu uccucugcac 6840cuuucccugc agaaucacag agauauagau ccucccuucc agggcaccag caccaauccc 6900ccuuugccuu uguucucuuc uccuucucua ggcuuuauuc auggcugcuc ccugaugccc 6960uucucauuug uuauuuuuua aagguucucc uagguaacug cuacaagagg cucuaagccu 7020gcaccagaau cucugcuugu cucuuguuua cuaugucauu agggcucauu cacagugaac 7080agaacccauu cuaccugguu uaagcagaaa gggacuucuu auaagauauu uaaugucuag 7140gccaggcgca guggcucaug ccuguaaucc cagcacuuug ggaggccaag guagguggau 7200caccugaggu caggaguuug agaccagccu ggccaacaua gugaaacccu gucucuacua 7260aaaaugcaaa aauuagcuga gcaugguggu gcacaccuau agucccagcu auuugggaag 7320cugaagcagg agaaucacuu gaacccagga ggcagagguu gcagugagcc aagauugugc 7380cacugcacuc cagccuggau gacagugaga cucugucuca aaaaaaaaaa aaaaaaaaaa 7440aaaaauuaau gucuuacaga augacuggag ggcagaagaa acagaauugc uacugagcuu 7500ucaggcauga cucccagugc cacaucacag acuuagguug acaagggagc ugcuguuccc 7560gccaggauca ggagauugug gaaucagaaa gcugccugcc uccugggaag ccauagugac 7620agcugcccag cuucagacuc augccaccuc uacuguuauc agacugaacu ugggucugcc 7680caccuagcac agcaaagcca aacauugaca cugggauugc agcaagagaa gugaggcauu 7740uauuacagga ugccaagcaa gaaggacugg gcagcuaaag cuuaggaccu gaacucccag 7800augguuugca guuaaggguu uuuaaaggca gggaggaaga uguuauaggc ugcuaugguu 7860ugguuuugug ucuccaccca aaucucaugu ugaacuguaa uuccuauugu ugggggaggg 7920acuugguggg aggugauugg aucauggggg uggacuuccg ccuugcuauu cucaugguaa 7980ugaguucuca caagaucugg uuguuuaaau auguguagca cuucccccuu ugcuuucucu 8040cgccugcucu accaugguaa ggcaugcuug cuuccccuuu gccuucugcc augauuguaa 8100guuucuugag accuuccagu cauacuuccu gucuagccca cagaacugug aaucaauuaa 8160acuucuuuuc uucauaaauu accuagucuc agaugucuug cucugucgcc caggcuggag 8220ugcaauggcg ugaucuuggc ucacugcaac auccaccucc cugguucaag cgauuuaacu 8280gucucagccu ccugaguagc ugagauuaca ugcaugugcc accaugccug gcuaauuuuu 8340guauuuuuag uagagaccag uuuucaccau guuggucagg cuggucucga acuccugacu 8400gcgugaucca ucugccucgg ccucccaaag ugcugggauu acaggcguga gccaccaugc 8460ccagccccuu cagguacuuc uuuauagcag ugugagaaua gacuaaugca caggcaaagu 8520uauaaaucag uucucacacu gcuauaaaga acuaccugag acaguaauuu augaagaaaa 8580gagguuuaau ugauucacag uucugccaag aacugaguuu gaacuugaac caauuuaaaa 8640acaccaauca gaaaucuugg gaagacaaau ugguuuggaa agugggaaga ggggaggugu 8700uuccugggca uguauuuauu uugaagcucu agugggacgu uccugaggag auaucaggga 8760gguaguuagu aauucagagc uggaacucua gagaaaagug aagcuggaga cagauuuggg 8820agucauguga gagagaggua gucaagggag ugcacguugu aggaacucaa uaaauguugg 8880uugaaugaca uaaccccguc acagcuggga ccagacuggc uaaaccauaa uuaguguuug 8940uagugagcag aaagagcaca uugguuuuug gccauaaagg agaagugagg gucuaggcau 9000ggagacuagg aauuaacaug aagcaacugc auaauuagca aauguagcag auauuuggau 9060ugguucauuu cagcuauucc aaucucuaag auagaaaaca aaaaaacuau auuuuccaga 9120uucccuugca gcuaggguuc cauauauaau auuuagauca uacccaucag augcagcgua 9180ccaaauuugg aaagcagaag uaaacaguug uaaggcaaga

acugugcuuu ggcuguuccu 9240acuaguaagc acaguggugg uaccuuuggu uuuucuauga cagauguaac agguccuaag 9300ucccagcccu auauucauag uugucaagag auaagacaca uaucauggua uugagaugga 9360guagggaccc ccccagcaug gaaauaaagg aaaaccuuga guuccuuuaa ggguaauucc 9420aagcaccugg cuagaacuca gaaguaaaug agcaauugga uaagcgagaa uguaauuguc 9480gcuuaaaaua gccaaggaag uuagagucau aagaauguuu gguucccugu agaaacuaaa 9540aauaaccuuu uuuuaaaauu uuagauggag ucuugcucug ucccccaggc ugaagugcaa 9600uggugcuauc ucggcucacu gcaauuuccg ccucuugggu ucaagcaauu cuccugccuc 9660agccuccuga guagcuggga uuaacgggca ccugucaaca ugcccggcca auuuuugcau 9720uuuuaguaga gacaggguuu caccacguug gccaggcugg ucuugaacuc cugaccucgu 9780gauccuucug ccucagccuc ccaaaagugc ugggauuaca gacgugagcc accgcaccug 9840gcaaaaauca ccucuuaaua uauguccuug aguuguuuuu uagaaaccug gaaccccaca 9900aaauggaucc ccuggcaugc agaccucagu cagauaaggg ggaacugagg acugaacucu 9960gaccacucuu ccuuuuuuca gauuucuucc uaaggggccu cgaggagguc acacccacaa 10020gccagagcua acauucuuac uacugauucc aaauuuuuag augaagcuuc gccuccuuaa 10080ccaauugcaa aucagaaaau cuuugaauuu accuaugacc ugugggcccc cuuugagaug 10140ucccaccuuu uuaggucaaa ccaauguaua gcccaggagc caacauguga gggaagaagc 10200cuucagguga uccagccucc agcuguugga gccaccauag cugagaugcc agauuucaug 10260gagcagagau gagccauccu cucugugcac aguccaaauu cuugacccag aaaaucuaug 10320agcacauuaa uggcuguugu uuuacuccac uaaguauagg gugguuugcu auauagcaau 10380aaggaaucaa aacaccccuc acauucaugu ugcuuauuau cugaugguua ucuuucacug 10440auaccaagca gcucauauuu uuaucuugcu caaaaaaccu uaaaugguuc ccccauugaa 10500uauggaauua auuauauguu cuuuaggcuu gcauucaaga uccugcucag uuuucaaucu 10560uacuaccuua ucuuucacuu uaacccgcua cucacuuuca auccacuugu accauauguc 10620agaucuucac ugggccacga cugaugcuuu ccuaucccug ugcccuuuca ccagcacugg 10680ccuuuugcuu ggaauugucg uuuucuauau uuaccaaauu ccuagcuauc auuccuucaa 10740gcucagugca aaucucacau ccuguaagac uuuguugccc aauguggugg ccaguagcca 10800cauguggcua uuuacauuua aaauagcacu gauuaaaauc uaaaguuuag uuccucaguc 10860ucacuggcca cuuuccgugc ucaggagcca caucccagug aacagcacug ucuuuuuagc 10920uuuuccuuuc ucaacuaauc ucuccuucuc ccauauaacc uuaaaacugc auuuuuagca 10980auuuugaccu gaauauuuuu gaggguugug uaauccaaau ccaugaaauu acagauacac 11040cuuggcuuuc uaccauucua gugcacugcu cuguaaaugg gagguggcuc aaauauuaau 11100ugaguuggga ggaagcagug guuaaucucu auacuauacu aaugggucug ggugaaauga 11160ccucuuauga ucuuuuccag uaaaauauuc aacaaacaac auaagucugu uaucuucaac 11220aauauauaau cuaucaggau agcuauuuuu uaaaucacag gugauuuggg aggaaggucu 11280cuugagagga gcauucugcc auucuggugu agcuguuucu guucucucca gcagcuauuu 11340uagguauuua auuauuuuag agugugugcu ugcauguguu uugucucaau guaugccaau 11400uuuuugccua guccuccuga caucuuaauc uaucugccaa cgcuacaugc cgucaagcca 11460aggaagaauu uccuucucac uguugcuucu cugaccaagg aagacauaag cacaaccaau 11520caccagacug augaaauucc uuccaguuuc agaaaagauu aucaccaauc ccuacauuau 11580aaaauucaua cuaauaaagc acaaacauug aauucuaaca u 116214221RNAHomo sapiensmisc_feature(1)..(21)Partial sequence of lncRNA12R tageted by siRNA 42caguggcugg uauuacagga a 214321RNAHomo sapiensmisc_feature(1)..(21)Partial sequence of lncRNA12R tageted by siRNA 43aaggaaaaag uucuccauaa a 214421RNAHomo sapiensmisc_feature(1)..(21)Partial sequence of lncRNA12R tageted by siRNA 44uagggagaag auaaucagau a 214521RNAHomo sapiensmisc_feature(1)..(21)Partial sequence of lncRNA13R tageted by siRNA 45cccccccagc auggaaauaa a 214621RNAHomo sapiensmisc_feature(1)..(21)Partial sequence of lncRNA13R tageted by siRNA 46uuccaguuuc agaaaagauu a 214725RNAHomo sapiensmisc_feature(1)..(25)Partial sequence of lncRNA8R tageted by siRNA 47ccaguccacu gaaccacauc cagaa 254825RNAHomo sapiensmisc_feature(1)..(25)Partial sequence of lncRNA8R tageted by siRNA 48gaacaguguu cacauucgcu ccuau 254921RNAHomo sapiensmisc_feature(1)..(21)Partial sequence of lncRNA12R tageted by siRNA 49gcaaaucagu guuggccauc u 215021RNAHomo sapiensmisc_feature(1)..(21)Partial sequence of lncRNA12R tageted by siRNA 50ggugucuaca uggcagcaua a 21

Claims

1. An lncRNA consisting of a nucleotide sequence having not less than 80% identity with the nucleotide sequence shown in any of SEQ ID NOs: 1-15 and SEQ ID NOs: 38-41.

2. An lncRNA that hybridizes to a complementary strand of a nucleic acid consisting of the nucleotide sequence shown in any of SEQ ID NOs: 1-15 and SEQ ID NOs: 38-41 under stringent conditions.

3. An lncRNA consisting of the nucleotide sequence shown in any of SEQ ID NOs: 1-15 and SEQ ID NOs: 38-41.

4. A nucleic acid consisting of a nucleotide sequence complementary to the lncRNA of claim 1.

5. A double-stranded nucleic acid consisting of the lncRNA of claim 1, and a nucleic acid consisting of a nucleotide sequence complementary to the nucleotide sequence of the lncRNA.

6. A nucleic acid that suppresses expression of the lncRNA of claim 1.

7. The nucleic acid according to claim 6, which is selected from siRNA, antisense nucleic acid, shRNA or miRNA.

8. The nucleic acid according to claim 6, which is an siRNA targeting the nucleotide sequence shown in any of SEQ ID NOs: 42-50.

9. A vector expressing the lncRNA of claim 1.

10. A cell introduced with the of lncRNA of claim 1.

11. A cell introduced with the vector of claim 9.

12. A cell growth promoter or growth inhibitor comprising the lncRNA of claim 1 as an active ingredient.

13. A diagnostic drug or a therapeutic drug for a disease caused by abnormality in cell growth, which comprises the lncRNA of claim 1 as an active ingredient.

14. The diagnostic drug or therapeutic drug according to claim 13, wherein the disease is selected from gastrointestinal cancer, liver cancer, kidney cancer, lung cancer, skin cancer, breast cancer, uterine cancer, prostate cancer, urinary bladder cancer, or head and neck cancer.

15. A method of detecting expression of lncRNA, comprising using the lncRNA of claim 1.

16. A method of detecting a mutation of lncRNA, comprising using the lncRNA of claim 1.

17. A method of suppressing expression of lncRNA, comprising using the nucleic acid of claim 4.

18. A method of screening for a substance that suppresses expression or function of lncRNA, comprising using the lncRNA of claim 1.